I'm Greg Kalemkerian, Professor of Medicine in Division of Hematology Oncology at the University of Michigan, and this lecture is going to be discussing small cell lung cancer limited stage. The objectives of the talk are to review the role of chemotherapy and radiotherapy in people with limited-stage small cell lung cancer. Reviewed the of prophylactic cranial irradiation, and review the outcomes of therapy in people with this disease. So, limited-stage small cell lung cancer is a potentially curable disease. Unfortunately, only about 30 percent of people present with limited-stage the others present with extensive-stage disease, which is incurable. Limited-stage is defined as disease confined to one hemithorax so, a tumor within the lung usually at the hilum of the lung, and then mediastinal lymph node involvement. But another part of the definition is that all the disease can be encompassed within a safe and tolerable radiation field. Sometimes this may include contralateral hilar lymph nodes or supraclavicular lymph nodes depending on the size of the field and the safety of treatment. The brain is unfortunately a common site of recurrence in small cell lung cancer and this fact will help guide some of our treatment decisions. We'll start with a pre-lecture question, 74-year-old smoker presents with cough, shortness of breath, and fatigue. Two months ago, he was very active but now needs assistance with daily activities. CT scan shows a large left hilar mass with bulky mediastinal lymph nodes. PET scan shows FDG-avidity in the left hilar and mediastinal lymph nodes and no other sites of activity in distance sites. MRI of the brain is normal, and an endobronchial biopsy of subcarinal lymph node reveals small cell lung cancer. What is the most appropriate further management? Platinum-based chemotherapy alone, thoracic radiation alone, concurrent platinum-based chemo plus radiotherapy or hospice care. So, we'll go through the lecture and come back to the question and answers at the end. There's a second part to the question. Upon completion of initial therapy, he recovers well with ECOG performance status of one. Repeat CT scans show mild left hilar soft-tissue thickening with no residual mass and no enlarged lymph nodes. MRI of the brain is again normal. Which of the following is the most appropriate next step in the management of this patient? Surveillance, Topotecan, maintenance bevacizumab, prophylactic cranial irradiation, or left upper lobectomy, and again, we'll come back to this question at the end of the lecture. So, for limited-stage small cell lung cancer, very few patients are eligible for surgery because surgeries only been shown to be beneficial in people with true stage one disease. This is less than five percent of patients because the majority of people have involvement of mediastinal lymph nodes. So, if people at stage T1-2 N0 disease, surgery is a reasonable option. It does require extensive preoperative mediastinal staging to make sure that the mediastinal nodes are not involved and the five-year survivals are generally considered in the 30-40 percent range with surgery. All patients who undergo surgery should have adjuvant chemotherapy as that does appear to improve overall survival. Thus far, we have not found any benefit to surgery in people who undergo definitive chemotherapy and radiation therapy. The primary treatment for people with limited-stage small cell is chemo radiotherapy with a platinum-based chemotherapy regimen concurrently with thoracic radiation. Chemo-radiation does improve survival over chemotherapy alone and thoracic radiation can be given either once daily or twice daily and we'll go through those results. Going back to some fairly old data, this is the meta analysis that evaluated studies which compared chemotherapy alone to chemotherapy plus radiation therapy. We can see that over a three year period of time, there is a five percent improvement in overall outcome. Now, remember that most of these studies were done in an era when we had very poor staging of patients, some of these were even before CT scans were utilized as a standard approach. So, this led to the standard utilization of chemo radiation as the usual treatment. Then we have the question of the sequencing of radiation and chemotherapy. So, the treatment can be done either sequentially, utilizing chemotherapy first followed by radiotherapy, or by doing them concurrently at the same time. We see that looking at overall survival, both two and five-year survivals are significantly better utilizing the concurrent treatment approach. There is somewhat greater esophagitis, acute toxicity, the late toxicity was not different between the arms. Another meta-analysis looked at patients who were all receiving concurrent chemo radiation but looking to see whether using radiation sooner in the course of chemotherapy versus later would be more beneficial and we see that there is a slight benefit overall in utilizing radiation earlier. So, now our general practice is to incorporate radiation with either the first or second cycle of chemotherapy in order to achieve optimal overall survival. What about fractionation? Fractionation of radiation refers to how many doses are given per day in an effort to try and speed up the treatment in order to prevent tumor regrowth during therapy. This is a study, an inter-group study done to evaluate this question. Looking at a control arm of once-daily radiation therapy to 45 gray, or an experimental arm of twice-daily radiation to 45 gray, given along with cisplatin and etoposide. This study did demonstrate a fairly large 10 percent improvement in five-year survival that was statistically significant with the use of twice-daily radiation though again, with an increased risk of esophagitis in these patients. Importantly, this study was done utilizing a fairly low dose of radiation, this 45 gray in the once-daily population. Forty five gray given once daily is not biologically equivalent to 45 gray given twice daily. So, it still did not definitively answer the question of which approach is better. A more recent study, the convert trial, tried to answer this question. So, in this study, patients with limited-stage small cell lung cancer a fairly large number of patients over 500, were randomized to receive either once-daily radiation to 66 gray. So, this is considered a more standard definitive dose of radiation versus 45 gray total dose given in twice daily fractionation. Again, all patients also received cisplatin and etoposide for four to six cycles. We see here that in the once-daily or twice-daily arm, there was no significant difference in overall survival. So, what the convert trial suggests is that you can utilize either once-daily or twice-daily radiation therapy concurrently with chemotherapy in order to try to achieve cure for patients with limited-stage small cell lung cancer. So, what have we learned about radiation therapy in small cell? Well, we've learned that concurrent chemo radiation is better than sequential chemo radiation. That doing concurrent radiation early in the course of chemo with the first or second cycle is better than late, and that with fractionation, we can either do once-daily to 60-70 gray or twice daily to 45 gray and achieve similar outcomes. With regard to chemotherapy, we have been utilizing this Cisplatin, Etoposide combination for many years now and it is relatively safe to do with concurrent radiation therapy. If patients have a contraindication to Cisplatin or have excessive toxicity with Cisplatin, then Carboplatin and Etoposide can be substituted. There is data suggesting that the two platinums are equivalent in small cell lung cancer even in limited-stage though the data is scant, and most of the information we have deals with Cisplatin in this potentially curative situation. We do know that the duration beyond four cycles is not appear to add any further benefit and a number of other strategies aimed at improving outcomes such as dose-intensification of chemo or using three drugs instead of two drugs have not been shown to improve benefit and do increase toxicity. So, I mentioned earlier that recurrences are very common in the brain with about 60 percent of people having metastasis to the brain, later in the course of disease. So, what can be done to prevent it? Number of studies have looked at prophylactic cranial radiation. In a meta-analysis of these studies published now almost 20 years ago, we see that prophylactic cranial irradiation does significantly decrease the risk of brain metastasis, cuts it in half essentially and does improve overall survival at three years which in this disease is essentially an improvement in the cure rate with a five percent improvement in overall survival. Now, importantly in these trials, the vast majority of people had limited-stage small cell lung cancer. So, I left an open question of does this data follow through in patients with extensive stage disease? And we'll talk about that a little bit later in the lecture on extensive-stage small cell lung cancer. So, for prophylactic cranial radiation, we do recommend that for people who had response to initial therapy with chemo radiation in limited-stage small cell with 25 gray in 10 fractions. For limited-stage, we know that there is a five percent overall survival improvement at three years which is sensory and improvement in cure rate. In extensive-stage disease, there does appear to be some improvement in one year survival but we'll talk about that in more detail later. We have to be careful in the elderly because there are unclear benefits and we know that once people get over about age 70 or so, there is greater neurocognitive toxicity. So, our standard treatment for limited-stage disease is chemoradiation with Cisplatin or Carboplatin and Etoposide for four cycles, with early concurrent radiation therapy started with the first to second cycle. Radiation therapy can be done either twice daily to a total of 45 gray or once-daily to 60, 70 gray. PCI does improve the survival of people who had had response. What do we expect to get with this treatment? We expect an overall response rate that is very high in the 80-90 percent range. Complete responses are found in about 20-40 percent of people with a median survival of about one and a half to two years and a five-year survival or a cure rate in the 20-25 percent range. So, coming back to our question, what is the most appropriate further management? The answer is concurrent chemotherapy and radiation therapy in order to achieve potential cure. Chemo alone or radiation alone has a lower chance of achieving such a cure. Hospice care is inappropriate for somebody who has potential curative intent and is in relatively good shape. The second part of the question after initial treatment, what else can be done for the management of this patient? And even though the MRI scan of the brain was normal, we do recommend prophylactic cranial radiation, given the good response to initial treatment and the known potential benefit of cranial radiation for improving the cure rate. So, the take home points here for this lecture are that limited-stage small cell is a potentially curable disease. Surgical resection is reserved for patients with stage one T1-2 N0 disease. Standard therapy is concurrent chemo and thoracic radiation. Chemo with Cisplatin or Carboplatin and Etoposide for four cycles and early concurrent radiation therapy. Prophylactic cranial radiation does improve survival and the cure rate is 20-25 percent. Thank you.
