[MUSIC] Welcome to module three, management of HPV-Associated Oropharyngeal Cancer. In this module, we're going to describe the options of management of HPV-associated oropharyngeal throat cancer, and some of the advantages and disadvantages of each option. In this module, we'll also discuss some of the indications and some of the contraindications for each modality of treatment. This is the treatment and impact of HPV status on throat cancer from a 2010 New England journal article. And what you're looking at here is the stratification of patients treated for oropharyngeal cancer. They break out into the low risk group the top, the intermediate group in the middle. And of course, the high risk group, the patients that do most poorly with this disease. They essentially stratify out into the upper or better half being HPV-positive, these patients respond best to therapy. In contrast, patients who have HPV- negative disease, respond less well. And in fact, patients with the HPV-negative disease have cure rates that are only around 40 to 50%. The stratification can even be further broken down by patients who smoke tobacco. For example in the upper group, the low risk group, you'll see that the patients that do the best are in higher rung or the upper half. However, patients who have HPV-positive disease, and they smoke 20 pack years, which is a pack per day over the course of 20 years, unfortunately do less well. This is similar in the HPV-negative group. In this group, the group does poorly compare to the HPV-positive group. However, those patients that smoke tobacco greater than 20 pack years, in fact even do less well. And so the stratification can be broken into four classes or four subclasses of patients. Each doing a little bit better or a little bit more poorly, depending on HPV status and tobacco use. There's three different approaches to treatment, when it comes to oropharyngeal or throat cancer. One is nonsurgical therapy and we'll talk a little bit about that. The second is surgical therapy and we'll review those options. And then finally, a combination of both nonsurgical and surgical therapy for a very select group of patients. Now, treatment options, when we talk about nonsurgical therapy, it's important to remember that most of the patients who present with this disease present in stage III or stage IV. That's to suggest that they typically present with a neck metastasis. Remember the tumor initiates or the primary site in either the tonsil, the basic tongue somewhere in the oral pharynx. But as soon as you have a metastatic lesion to the neck, a tumor in the neck that becomes stage III disease. And as a result those patients typically require more advanced tumor aggressive therapy. A typical therapy for a patient who receives nonsurgical therapy, chemotherapy and radiation, is 7,000 centigrade radiotherapy with systemic or intravenous chemotherapy. Now it's important to recognize that this treatment protocol was designed for patients with HPV-negative disease. That's patients that have a significant risk of tobacco and alcohol use. Those patients are typically in the 7th decade of life, around their 70s or 80s. And they have very aggressive diseases that doesn't respond well with therapy. As a result, these patients require extensive and high doses of radiation with systemic chemotherapy. And you can see here those patients receive a special planning, where three dimensionally the tumor is targeted with a radio therapy. And they're placed in a mask to keep them from moving throughout the therapeutic dose. If you look at this dose treatment or treatment response curve you'll see that on the x axis, 7,000 centigrade radiation is associated with a rather high toxicity which you see on the y axis. What we're trying to do is match the treatment with the type of disease. This is the typical dose that we give for patients with high risk disease. HPV-negative and in some cases, patients who smoke tobacco or drink alcohol in excessive doses. Now, if you'll look at the 7,000 centigrade dose of radiation, you'll see how high the tissue toxicity is for these particular patients. Most would argue that these patients require high doses and high toxicity, unfortunately that accompanies it, because the disease is deadly. Unfortunately, there's significant treatment toxicity associated with this high dose of radiotherapy. And the treatment protocols, as I mentioned, that were applied to HPV-negative patients are the same protocols that now unfortunately are being applied to HPV-positive treated patients. Now, the high dose is associated with excessive burns to the neck as you can see in the upper panel. Those burns are often full fitness so they not only affect the skin as you see in this picture but they in fact affect the muscle and the deep tissues as well as the inner lining of the throat. Over the course of time, these burns will become scar tissue, and that scar tissue makes swallowing very difficult. When you couple this with the lower panel, which is loss of saliva and the loss of taste, this can be rather debilitating. Over the course of time, the impact on saliva, the impact on swallowing, muscle, the inner lining of the throat. You can get as high as 11 to 20% to patients that required a gas proximate tube for nutrition. Some of these patients were also required a tracheostomy permanently to protect their airway from aspiration. Needless to say this treatment approach although many times necessary for the very ill patient carries with it significant toxicity. We look back at the dose response curve that we referred to earlier and we talked about the 7,000 centigrade dose of radiotherapy used for the HPV-negative patient. If you look, what we're often trying to do in the HPV-positive patient is reduce the dose of radiotherapy, shift that curve from the right to the left. And you can see, as you shift that curve to 6,000 centigrade, you'll notice on the y axis a significant drop or dip in the toxicity associated with the tissue damage. That's what we're trying to achieve because this is the group, the upper panel, the lowest group that we're treating here. It's our belief and the belief of many investigators that we don't require high dose therapy for this younger population with a disease type that tends to respond much better to therapy. Again, this shift from right to left is what we're trying to achieve, and the reason we're trying to achieve it is because of quality of life and function. You're looking here at a graph that demonstrates the quality of life, the impact on function. Swallowing and general happiness and it's affect through the course of chemoradiotherapy over one year. You can see that the quality of life starts out quite well and then takes a dip as we initiate radiation therapy. Through the course of one year, function and quality of life improve. But if you'll notice, the level of quality of life never completely reaches the initial level of quality of life prior to treatment. That's because you're dealing with the very high dose and a very toxic approach to therapy. In contrast, if you look at the surgical approach you'll see a drop in quality of life associated with the surgery in the x axis. You'll see a slow improvement and then a drop again as we began radiation therapy three to four weeks after. But then there is a progressive rise in quality of life up to the quality of life that's associated with pre-treatment levels. So what is the difference between these two treatment approaches? It's a drop in the radiation dose, at least that's what most investigators believe. In this younger patient population, if we can reduce the toxicity of therapy the quality of life, function, swallowing, general happiness improve over the course of one year. This shift in the curve from right to left as you see from 7,000 to 6,000 is associated with this increase in quality of life over the year's time. This is a very important concept, because the concept relies on the fact that young patients have a long, long time to live. A typically HPV-positive patients do not form the same group as HPV-negative patients, which tend to be older. So we want to do everything we can to improve their quality of life and their function. Not just in the acute period but over the long haul, 20, 30, 40 years. The surgical options for the most part, up until the last decade had been open surgery. This can be a morbid surgery as you can see in the lower panel on the right. This is a big procedure that takes 12 to 13 hours. These patients who undergo open surgery can be in the hospital 10, 12, 14 days. However, over the last decade, there's been a shift to robotic surgery or minimally invasive surgery. This is a very different approach that allows us to place the robotic instrumentation through the mouth without ever having to make an incision through the lip or the through the mandible. Instead of this being a 13 hour surgery, this is now a 2 hour surgery. And instead of being in the hospital under observation and management for two weeks, most patients are home eating and swallowing within a day or two. Pretty remarkable change and a change that's appropriate for this disease and appropriate for a younger patient population. What you're seeing here is a video of transoral robotic surgery. You'll see the robotic instrumentation which is placed into the patient's throat and mouth. You'll see an assistant sitting by the side guiding and up in the upper right panel, you'll see what robotic surgery is really like. This is essentially a bloodless dissection and removal of the tumor without ever having to make an incision in the lip or chin. In the lower panel, the console behind you is where the surgeon sits. And that surgeon directs the surgery and directs the robotic arms. Throughout the course of the surgery, we're able to, with very fine manipulation and very fine dexterity, remove the tumor and essentially a bloodless plain, which allows us to get the tumor out, and get the patient back to his family or her family with excellent functional outcomes. In summary, HPV status has a significant impact on survival. You have to think back to the dose response curves as well as the survival curves that we showed early on. Unfortunately, HPV-negative disease and even worse HPV-negative disease in tobacco users those patients don't do particularly well. Most of this discussion is focused on the HPV-positive patients, the young patients who have no tobacco history or a minimal tobacco history and those patients do very well. As a result, we want to curtail therapy to the disease. HPV-positive disease has a much better outcome than HPV-negative disease. And the old treatment algorithms aren't necessary applicable in this position in this situation. Now the treatment options for oropharyngeal cancer can include a combination of chemotherapy and radiotherapy, or minimally invasive surgery or the utilization of all three modalities. The key is matching the appropriate therapy with the appropriate patient. Most of the minimally invasive approaches that we talked about today are performed on trial. A places like the Mount Sinai, Head to Neck Institute, where the trials are carefully monitored and carefully controlled to ensure that the patients are treated appropriately, given their level and significance of disease. Finally, the goal of therapy is to achieve a cure with minimal impact on function. If we can maintain high cure rates but improve the long-term and short-term outcomes in the functions of our patients, then we've done a good job. These are done through de-escalation protocols that may improve the quality of life but maintain very high cure rates. The de-escalation protocols as we referred to them are when we have the opportunity to mitigate the need for radiation therapy altogether, lower the dose for radiation therapy, or mitigate the need for chemotherapy. We're able to do this in about 40% of patients that are currently on trial, simply by removing the tumor through minimally invasive techniques. Again, most of these should be performed on trial. Thank you very much. [MUSIC]
