I'm Greg Kalemkerian Professor of Medicine in the Division of Hematology Oncology at the University of Michigan, and this lecture is going to deal with the management of people with extensive stage, small cell lung cancer. The objectives of the talk are to review the primary role of platinum-based chemotherapy and people with extensive-stage disease. Review the role of thoracic radiation and prophylactic cranial irradiation, and to review the outcomes of treatment in people with this stage of disease. Extensive-stage small cell is a incurable disease. Unfortunately, about 70 percent of people with small cell present with extensive-stage disease. Extensive-stage is defined as disease that is beyond limited-stage. This includes either pleural or pericardial effusions, contralateral lung lesions, or hematogenous metastases. The brain is a very common sight of metastasis in all patients with small cell lung cancer. We'll start with a pre-lecture question. Fifty six year-old man presents with dyspnea, abdominal pain and weight loss. He spends most of his day sitting in a chair. He has a 60 pack-year smoking history but no chronic medical problems. His exam reveals moderate painful distress, dyspnea on a minimal exertion, decreased breath sounds, and rhonchi in the left lung, and firm, nodular hepatomegaly. CT scan shows a five centimeter left hilar mass with narrowing of the left mainstem, bulky bilateral mediastinal and hilar lymph nodes, and numerous metastases within the liver. A core biopsy of the liver reveals small-cell lung cancer. Labs reveal normal counts, normal renal function, and mildly elevated alkaline phosphatase with otherwise normal liver function tests. An MRI scan of the brain shows no metastases. Which of the following is the most appropriate next step in treatment? Thoracic radiotherapy followed by Cisplatin and Etoposide, concurrent platinum Etoposide, and radiotherapy. Carboplatin and Etoposide, single-agent oral Etoposide, or supportive care with hospice services. We'll go through lecture and come back to the question and answers at the end. So, the standard chemotherapy regiments for extensive-stage disease are platinum-based regiments, primarily Cisplatin, on Carboplatin and Etoposide, or Cisplatin and Carboplatin, or Carboplatin plus Irinotecan. With this treatment, we do know that there is an improvement in survival. Before chemotherapy was utilized for this disease, the survival was very short measured in the range of one to two months. In people who receive platinum-based chemotherapy, the median survival is now prolonged up to 9-10 months and while that is far too short, it still is a significant improvement with the use of chemotherapy. There are a number of newer chemo regiments that have been explored in primarily Phase II studies, and we see those listed here on this slide, a variety of combinations of 2 and 3 drug regiments. All of which yield response rates that are in the same range as what we expect to see with a platinum Etoposide standard treatment, and there are actually even our radiographic complete responses in about 10 percent to 20 percent of patients. So, small cell is a very responsive disease to treatment, the problem and extensive-stage is that it does recur and tends to recur in fairly short order. So, this is an example of several randomized controlled trials that explored the question of Irinotecan and Platinum versus Etoposide and Platinum. We see in the first trial that was done here that there was a significant improvement in survival at one year for people receiving Irinotecan Cisplatin, but in that study was done in Japan and was stopped early for the positive result. But in other studies done in the Western populations, we see that there is no difference in survival between Irinotecan or Etoposide along with Cisplatin. Based on these studies overall does not appear that there's an improvement in survival with Irinotecan and the Western population. Possible explanations are that the Western and Japanese patients may metabolize the drugs differently so pharmacogenomics may play a role, or that the Japanese Cancer Oncology Group study was stopped early with small sample size that may have detected a large treatment difference by chance. So, Etoposide and Platinum remains the standard treatment for small cell lung cancer in the United States. For a long time we've had the question of whether or not we need to use Cisplatin. Cisplatin is a more toxic drug than Carboplatin with more non hematologic toxicity associated with it. So, in a palliative situation, it is a drug that does not make a lot of sense unless it's significantly better than the alternative. There is a meta-analysis published several years ago that looked at the four trials that compared Cisplatin containing regimen to a Carboplatin containing regimen in patients with small cell lung cancer both limited and extensive stage disease, and demonstrated that there was no significant difference in progression-free, or overall survival, or any difference in response rate between Cisplatin and Carboplatin containing regimens. So, it does appear that Carboplatin can be a good substitute for patients with small cell lung cancer, and in the extensive stage situation in which palliation is the goal, I would argue that Carboplatin is the preferred drug. So, many other chemotherapy based strategies have been evaluated in extensive-stage small cell lung cancer, and none of them have demonstrated a consistent improvement in outcomes, and many of them have shown excessive toxicity. So, alternating regiments, maintenance therapy, dose-intensification, three drug regiments, consolidation chemo, and dose-dense chemo have not been generally accepted as beneficial. So, I mentioned earlier that about 60 percent of people with small cell will develop brain metastases. Can we do anything to try and prevent that or lower that rate? Well, this meta analysis done a number of years ago, did demonstrate a significant improvement in survival for people undergoing Prophylactic Cranial Irradiation after initial treatment for small cell lung cancer, but the meta-analysis included the vast majority of people with limited-stage disease. So, I left open the question of whether or not this data translated into extensive stage. So, the EORTC undertook a trial in which people with extensive stage small cell only, received first-line chemo. If they had any response to treatment, they were then randomized to receive prophylactic cranial irradiation with a variety of different allowable doses and regimens, or no radiation to the brain. Now, importantly in this trial, they did not require imaging of the brain prior to this randomization. So, it's possible that some of the people who got PCI actually, were not getting prophylactic radiation, but were getting therapeutic radiation because they now had brain metastases, and possible that some people with brain metastases were not getting appropriate radiation therapy in the control on. The results of this trial demonstrated a significant decrease in the risk of brain metastases with PCI, which is not unexpected, and an improvement in overall and progression free survival with about a 14 percent improvement in one year survival. So, this is not improving the cure rate, but it clearly is helping to prolong survival in some patients with this disease. In Japan, the West Japanese oncology group, also did a study looking at prophylactic cranial radiation in people with extensive small cell lung cancer. So, they took people who had received platinum-based two-drug therapy. In people who had any response to treatment, and who were shown to have no brain metastases by MRI assessment, they were randomized to receive PCI in a standardized fractionation and regimen scheme here of 25 gray in 10 fractions, which is a standard approach, or no prophylactic cranial irradiation. Importantly in this study, all patients were followed up with very intensive MRI imaging, in order to try and identify asymptomatic brain mets at a stage where they can be treated without excessive morbidity to the patient. This trial was conflicting with the European data, in that there was no significant improvement in survival with PCI. In fact, if anything, the survival curves trended towards favoring observation. Similarly, there was no difference at all in progression-free survival. So, we now have two trials with very different outcomes, one of which demonstrated a significant benefit to PCI, and one which did not in people with extensive stage disease. There were differences in that, brain imaging was not required in the EORTC trial, there were a variety of regimens in that trial, both trials said a response or any response, they did not clearly defined what a response meant. Importantly, and most importantly I think, in the Japanese trial they did very intensive MRI surveillance of the brain of three, six, nine,12,18, and 24 months. What this does is help to identify people before they get symptomatic from their brain metastasis, so they can be treated more aggressively with therapeutic radiation. Also interestingly, the survival outcomes in the EORTC trial were rather poor. Particularly, in the control arm, they were worst one year survivals than what we would expect for extensive stage small cell. Whereas outcomes in both arms of the Japanese trial were excessively good, a little bit better than what we might expect for people with this disease. So, other than radiating the brain, another strategy that's been explored is radiating the chest in a consolidative manner, in order to try and decrease the morbidity of having recurrences of cancer within the chest after initial therapy. This was another trial coming from Europe, again published by Dr. Slotman. This study looked at people with extensive stage small cell who had responded to initial platinum-based chemotherapy, who had no brain metastases, and a relatively good performance status, who were then randomized to receive either thoracic radiation NPCI, or just PCI. The radiation to the chest was palliative in nature with 30 gray in 10 fractions, aimed to start within weeks of the chemotherapy initial treatment. Primary endpoint was interestingly one year overall survival. Now, the primary endpoint was not met. The primary endpoint was negative, did not demonstrate a benefit in one year overall survival, though there was a trend. But, at two years, there was a significant improvement in survival with thoracic radiation therapy. So, what is our standard approach now for people with extensive stage small cell? The chemotherapy is the base of treatment with Carboplatin and Etoposide for four cycles. After that, we can maintain with MRI surveillance of the brain or PCI for responders, and now I am favoring the MRI surveillance of the brain. So, we are only treating those who require treatment. Importantly, most patients will require brain radiation at some point in time for brain recurrences, and we can consider thoracic radiation in order to try and decrease the morbidity of intrathoracic recurrences such as, shortness of breath, coughing, and discomfort. What do we expect? We expect high response rates, small cells of very responsive disease to chemo, responses in the 50 to 70 percent range. We expect complete responses in about 10 percent of people, but these responses are not durable. People recur with a median survival of only nine to 10 months, and a very rare patient will survive beyond five years. So, now we come back to our post-test question. A Patient with some performance status issues, about performance status two at this point and time. Though, has good laboratory values and a negative brain scan, and which is the most appropriate next step in management. The answer is Carboplatin and Etoposide. We would not use an aggressive chemo radiation approach up front, as there is no evidence of benefit for people in that situation and excessive toxicity, and supportive care is not appropriate since he has a good chance of improving his quality of life, and giving him some period of time in which to accomplish his goals. So, the take home point here, is that extensive stage disease is incurable with a goal of palliation. So, we want to use the lowest toxicity chemotherapy that will improve outcomes, such as Carboplatin and Etoposide that has a high response rate, and does improve survival. PCI remains controversial and I'm favoring MRI surveillance at this point over PCI. Thoracic radiation can improve survival and may improve morbidity of recurrences after initial chemo radiation. We know that future advances in this disease are likely not to hinge upon chemotherapy, but are more likely to be dependent on molecularly targeted therapy, or immunotherapy approaches that we'll talk about in the next lecture, in relapse and refractory small-cell lung cancer. Thank you.
