Hello, my name is Susan Urba, I'm a medical oncologist and I specialize in the treatment of The esophageal cancer. I'm also a palliative care physician and I specialize in the treatment of pain and symptom management for patients. I've prepared six modules from the medical oncology's perspective of treating esophageal cancer. This module will talk about the treatment of local regional disease. The objectives of this module are to understand the possible variations in rationale for combining the 3 modalities of treatment for local/regional esophageal cancer. These include surgery, chemotherapy in various forms. Pre-operative, peri-operative, post-operative, and then with or without radiation therapy. So I'll go through these five areas and try to explain the rationale for them. And just a preview, there are many possible treatments for local, regional, esophageal cancer. So let's look at a pre-lecture question. What is the preferred treatment approach for locally advanced esophageal cancer in the United States? A, concurrent chemo plus radiation. B, chemotherapy before and after surgery. C, concurrent chemoradiation followed by surgery. Or D, surgery alone. So take a moment to think about your answer and then see if you can find the right answer as we talk about these various modalities. Surgery, chemo and radiation are the topics we'll be talking about. So let's start with surgery, the most common approach is called the Transhiatal Esophagectomy, there is a picture shown here, where an incision is made right in the lower aspect of the neck, and right below the xiphoid process. An incision is made at the top of the esophagus and the bottom of it. The surgeon's hand is then put into the mediastinum, and he literally scoops out the resected esophagus and the lymph nodes and then sutures the two ends back together again. In the past, the chest use to be cracked open so to speak, which is thoracotomy, but this particular approach avoids that, there's not such a big surgical incision. By doing cervical anastomosis, there's less morbidity because if a leak occurs, and it sometimes will. They can just open up the little suture line in the neck and let it drain and then heal up. If the anastomosis was in the media stynum and a leak occurred, you would get what's called media stenitis, which is an infection in your chest. It can be very serious. So this is really a less morbid surgical procedure. Blunt resection, as we said, of the esophagus from the esophageal hiatus and thoracic inlet and actually the patient is out the door in about seven days swallowing, so usually they tolerate it quite well. So that's the surgical part, so let's talk about what's the role of chemo and/or radiation therapy. So preoperative chemotherapy has been looked at. A very large trial in Britain with 800 patients with localized esophageal cancer, where we endomized to receive either surgery alone or chemotherapy for a couple of cycles before surgery. The results are shown here. They reported their results in 2002 and then an update in 2007. And you can see that the two year survival rate, which was reported in 2002 was better for those who got chemo and surgery. 43 versus 34%. When they updated this in 2007, the five year survival rate was still significantly better. Then, another trial was reported, looking at just chemotherapy. But this time before and after surgery. The three cycles of chemotherapy were called ECF. Epirubicin, cisplatin and fluorouracil where first given to the patient, then surgical resection. And then more of the chemotherapy. When they looked at the difference in survival, the hazard ratio was statistically significant in favor of those who had gone to chemotherapy are to a P value of 0.009. And a meta-analysis was done looking at the role of chemotherapy in esophageal cancer. It looked at 9 trials, more than 2000 patients. And they took all the individual data and put it all together in the meta-analysis and it did look like there was an improvement in the hazard ratio of 0.87 with the p value of 0.003. So what this actually mean to the patient that at 5 years typically the survival would have been approximately 16% and there was survival increase of 4% to about 20% if chemotherapy was used. So in the NCCN guidelines, NCCN is national comprehensive cancer network, which is a group of cancer centers across the country that come together to write guidelines for standards of care and they do accept peri-operative chemotherapy, as a potential and reasonable treatment for adenocarcinoma of the esophagus. However, I'll show you future data, that will incorporate radiation therapy, which we tend to use a little more in the United States. But this is a reasonable treatment. And this approach is quite commonly used in Europe. So let's talk about the addition of radiation now to chemotherapy. There was a large study reported from the Netherlands. A randomized trial reported in the New England Journal of Medicine which looked at patients who were treated with surgery alone versus pre-operative chemotherapy and radiation. They received weekly treatment with chemotherapy for five cycles, consisting of Carboplatin and Paclitaxel. They also received daily radiation, then surgery was six weeks later. So how did these patients fair? The who got the chemo radiation and surgery had better median survival, 49 months versus 26 months and this was statistically significant. And then, when they recently reported an update, those differences held. The patients were still doing better if they had received chemoradiation and surgery. And it was true for both cell types, Squamous cell and Adenocarcinoma. So again, a met analysis was done I could talk about many, many trials, but I'd like to just give a quick overall summary here. So a meta-analysis looked at 12 trials, with 1,800 patients who were treated with variations of pre-op chemoradiation Chemoradiation versus surgery alone. Again, the survival was improved with the addition of chemoradiation and this was also true for both squamous cell and adenocarcinoma. So the NCCN Guidelines also include pre-operative chemoradiation as a good approach for esophageal cancer. This does tend to be our preferred approach in the United States. There are several different regimens that have been tested in randomized trials that are very reasonable to give as part of the treatment. I only talked about the one specific trial. Using Paclitaxel and carboplatin. But there are other variations also. So we've talked about two possible treatments for esophageal cancer. Let's see about a third. Post-operative chemo radiation. So what about those patients who go through surgery first? Should they get post-op treatment or not? A large study was conducted as part of the intergroup 556 patients first had surgery for either stomach or esophageal cancer. And they were randomized to what was considered standard of care at that time. Just observation versus getting Post-op chemoradiation. There was an improvement in median survival, 36 months versus 27 months. And in three year survival, 50% versus 41%. Therefore, this has also been added into the guidelines as a possibility for treatment. Surgery followed by post-op chemoradiation. And then the specifics of the treatment are spelled out here. Unless you're really going into medical oncology, I think knowing the general overall concepts are what's important here. And last but not least, how about non surgical therapy? How about just chemo and or radiation alone? A trial was reported by RTOG, which is the Radiation Therapy Oncology Group. And updates were reported three different times. They looked at a group of patients who were random, who did not go through surgery. They were randomized to either radiation alone, versus radiation plus chemotherapy. And the chemotherapy was Cisplatinum and 5 Fluorouracil. The patients who got the chemo radiation did better. If you first look at the bottom part of the slide, median survival was 14 months versus nine months. And at five years, 26% were alive if they had gotten chemo radiation. And no one was alive if they got radiation alone. So, definitely if the patient can tolerate it, they should get chemoradiation. But not everybody can tolerate it. If you now look at the top part of the slide, where it talks about toxicity, severe toxicity was 44% versus 25% and life threatening toxicity was 20% versus 3, if they had chemoradiation. So for those patients who are fairly frail and you're a little worried about getting treatment into them. There may be a role for radiation alone, even though it is less efficacious it is also less toxic. So what are the conclusions for nonsurgical therapy? It's the best treatment for bulky inoperable disease or for patients who are medically not surgical candidates. Let's say the patient had an MI, maybe a couple of weeks ago. They should not go through surgery for many months. So then those patients typically treated with chemo and radiation. So if they're going to get non-surgical therapy, it should be chemo-radiation, if possible. But radiation alone may be the best treatment for frail patients or those with very poor performance status. So the NCCN guidelines acknowledges this also and says it's a standard of care if patients are medically unfit or if surgery is not elected. I've had patients just refused surgery. And then if you do give chemoradiation there are very specific regimens that have been tested and are effective. So, in summary, surgery alone is a good treatment for stage one which is very early disease. Or sometimes those patients are included in clinical trials. And sometimes they're even being looked at for photodynamic therapy if it's a very small lesion to see if we can get away with less rather than a full Transhiatal esophagectomy. Stage II or III, which is probably the most commonly seen group of patients. As we saw there are several standards of care. Peri-operative chemo is a good standard of care, not commonly used in the U.S. for whatever reason, but more commonly used in Europe and Asia. Pre-op chemoradiation is a standard of care. It tends to be our preferred treatment. But patients must be able to tolerate an aggressive regimen. Chemo and radiation, and surgery is a lot to go through. Also for Stage Two or Three disease, post-op standard chemoradiation is a standard of care. Sometimes occasionally a patient will be undergoing an endoscopy, still as they're staging workup and if a perforation occurs, that patient has to go immediately to surgery. So then, after surgery, then we have to deal with the patient. What do we do next? Most typically, we do follow up with post-op chemo radiation. And then, once again, definitive chemo radiation for those that can't get surgery. So let's return to our post-lecture question now. What's the preferred treatment approach for locally advanced esophageal cancer in the United States? Concurrent chemoradiation, chemo before and after surgery, concurrent chemoradiation followed by surgery, or surgery alone. So take a minute and write down your answer. Hopefully you got the right one. Concurrent chemo radiation followed by surgery is the most typically used regiment in the United States. So, our summarizing take home points are, there are several options for treatments of patients, so we really have to look at each patient individually to figure out which is most appropriate. Preoperative chemoradiation is most typically used, but perioperative chemo is acceptable as is post op chemo radiation. Definitive chemoradiation are reserved for those who are medically unfit for surgery or who refuse it. So I think you very much for listening to this module. And hope you will listen to the rest of them also. Thank you.
