First of all, the pathophysiology

Transcription

1 Welcome. My name is Eric Sturgis and I m a Professor in Head and Neck Surgery with a joint appointment in the Department of Epidemiology at The University of Texas MD Anderson Cancer Center. And today we re going to talk about oropharyngeal cancer and the clinical implications of the HPV epidemic. I would like to point out that we have two other talks, one covering the importance of HPV vaccination and another one specifically going through the details of the epidemic in HPV-related cancers. So our objectives today are to first describe the pathophysiology of HPV infection and malignant transformation; to understand the clinical differences between patients with HPV-positive oropharyngeal cancer and those with HPV-negative oropharyngeal cancer; to understand the clinical implications of this disease; and to describe some of the current trials that are presently available. First of all, the pathophysiology This cartoon represents how HPV infection is --- is known to occur and --- and how the prog --- progression from an infection to ultimately an invasive cancer shown here on this side of the screen occurs. Typically it s felt that there is some sort of break in the superficial layer of the epithelium such that the virus has access to the basal layer of the epithelium. And those are the cells in which the virus grows and propagates and uses the shell ma --- excuse me --- the cell machinery to --- to produce more virus which is then shed into the mucus secretions allowing for infection of other individuals. During this process, cellular changes can occur from a low-grade state, a pre-malignant state, shown here as cervical intraepithelial neoplasia 1 and eventually to more high-grade, more aggressive appearance that is shortly before it becomes an invasive cancer. This process can take years of time to develop. Ultimately cancer occurs when a portion of the viral DNA becomes integrated into the human cell and into the human cells DNA and then a malignant transformation occurs and ultimately an invasive cancer shown here. When this happens, typically the infectious phase is over actually having been cleared many years previously and an invasive cancer then is present. On a cellular level, this cartoon depicts what happ --- what happens with viral infection and endocytosis occurring, and the virus getting into the cell, ultimately into the nuclei. And the process by which the viral DNA, an important part of the viral DNA typically the viral onco --- the DNA coding for viral oncogenes E6 and/or E7 get integrated into the human DNA, depicted here. Then the human cell is actually producing E6 and E7 messenger RNA and eventually the proteins E6 and E7 which have the cancer causing effect of --- for E6, increased degradation of p53 shown here and in the lower portion here affecting the Rb pathway. What s important here is a marker for HPV-driven cell and particular HPV-driven cancer, as you will see upregulation of the p16 protein as a feedback mechanism of the Rb pathway being shut down. How do these patients present? Well these --- this slide shows the largest series to date showing the initial symptoms of oropharyngeal cancer patients that are HPV-related versus not HPV-related and certainly

2 others have shown similar findings in different series. Typically these patients, over half of them will present with a neck mass rather than the typical findings for head and neck cancer of pain, painful swallowing, pain in the ear, sore throat, trouble swallowing, or weight loss. So those are more typical of tobacco-related head and neck cancer. While HPV-related cancer typically presents without symptoms in the throat and more commonly with essentially a lump in the neck. Also I should note and most of these patients are men. 80% of them are men. Typically they are white men. They are typically in the 40s and 50s with a median age of 55. And they tend to have a higher socioeconomic status than HPV-negative patients. HPV-negative patients were --- are historical --- what we ve seen here at MD Anderson. This represents all patients with newly diagnosed oropharyngeal cancer at The University of Texas MD Anderson Cancer Center going back to its --- its early days in And we can see traditionally the overwhelming majority of our patients similar to traditional head and neck cancer were currently smoking. And I don t show it on this slide but they were also current drinkers, a typical pattern for head and neck cancer. But in the last 10 years, after 1995 when --- when most series support that there was more and more of these cancers were related to HPV, we found that almost two-thirds of our patients were never smokers or had a history of being former smokers. And shown here in the lower part of this table patients that were smokers more likely were less tobacco or less current pack years of smoking than in previous years when they tended to be very heavy smokers presenting with oropharynx cancer. How about the location of these cancers and their staging at presentation? Just in summary, they tend to be lower T stage or the size of the tumor in the throat tends to be rather small. Oftentimes they are not visible or only identified after careful inspection and --- and sometimes some special studies. The lymph nodes, as I showed in the previous slide, they usually present with lymph nodes so they tend to have a higher nodal category or --- or N stage. They also tend to be higher in their grade. Und --- Histologically, they tend to be more poorly differentiated than traditional head and neck cancer. And they tend to be of the tonsil and the base of the tongue rather than the soft palate, the uvula, or the pharyngeal wall. So the base of the tongue is what we refer to as the very back part of the tongue, the lingual tonsil it s sometimes called, or the --- the pharyngeal or throat part of the tongue. It s the part of the tongue you cannot see just with anterior examination of someone s mouth. This is a large study from colleagues in Toronto showing that 91% of the HPV-positive group were of the tonsil or the base of the tongue as opposed to only three-quarters of the HPV-negative group and they tended to have not --- tended to not be of this large T-category, T4, and they tended to not be in zero meaning no lymph nodes. They tended to have lymph nodes and have smaller primary cancers. And their overall stage, mostly driven by the fact that they have multiple lymph nodes, they tend to be stage 3 and 4. So 93% in their population of HPV-positive patients were stage 3 or 4 as opposed to only 80% of the HPV-negative group. At MD Anderson, again, this is a table depicting the --- the history of MD Anderson. We can say in the most recent decade after the cut of 1995, which we consider sort of a --- a nice period in which we can define HPV-negative period to HPV-positive period, 86 of our

3 patients % of our patients after that time point were of the tonsil or base of the tongue. Most of them tended to have smaller primary cancers. They tended to have larger lymph nodes or more lymph nodes. And 88% of our patients in the HPV period tended to be stage 3 or 4. So how about prognosis? This depicts 5-year survival rates in our National Cancer Registry. This is the SEER Cancer Registry. It is not --- doesn t cover the United States universally, but there are 18 sites throughout the country in which the data is gathered on cancer. And we have information from that which is projected to the country as a whole for cancer incidence, cancer mortality, and in this case 5-year survival rate. So this is population level survival rates if you re diagnosed with either larynx cancer or cancer of the voice box, oral cavity cancer or cancer of the mouth, or oropharynx cancer or the cancer we re talking about today, cancer of the tonsil, base of tongue, soft palate. And you can see prior to this 1995 year, oropharynx cancer had the worst survival of what we consider traditional head and neck cancers. Qu --- Quite dramatically different than either larynx cancer or oral cavity cancer. But as this epidemic took place, we now see that in the most recent time period and I can tell you if you go forward a couple more years from this oropharynx cancer clearly has the best five year survival rate as --- as a head and neck cancer site in our country. This is MD Anderson and each of these curves show the cumulative proportion surviving. And this is time from treatment along the bottom --- or excuse me --- time from presentation to MD Anderson along the bottom. Each of these different colors represents a different decade of treatment. And you can see while we did have some improvement each decade in oropharynx cancer survival at our institution, it was really dramatic after 1995 that we saw really a dramatic increase in 5-year survival rates for these patients. And that s consistent with the national numbers. It s also consistent with a supposition that HPV-related cancers do better. But it was really this study in 2008 published in the Journal of National Cancer Institute, a landmark study which was a clinical trial --- a prospective randomized --- excuse me -- - a prospective Phase II clinical trial which showed that HPV-positive patients did better than HPV-negative patients in a group of patients treated in a very standard fashion all the same way, presenting with very similar stage cal --- classification. And that was true for overall survival and progression-free survival. And since that time we ve had at least phase --- excuse me at least four Phase III studies shown here which also showed in each of these trials which were randomized Phase III multi-institutional trials --- cooperative group trials which showed that while the two treatments being compared in each of these studies did not differ in oropharyngeal outcomes. Patients with HPV-positive cancer clearly did better shown here with hazardous ratios here in both overall and progression-free survival in each of these four studies. So this is now very strong evidence that HPV-positive oropharyngeal cancer do

4 better than HPV-negative oropharyngeal cancer with various forms of treatment in these four different Phase III clinical trials. Now staging for oropharynx cancer is --- should, as staging is supposed to do, should stratify patients on their prognosis and the staging for oropharynx cancer is essentially based upon the size of the cancer in the oropharynx for the T stage or T category and the --- either presence or absence of lymph nodes and then the number or the extent of lymph node involvement for the N category. The combination of T and N gives us the overall stage. So before 1995 I wanted to show you this. This is MD Anderson. We can see that stage 1 and 2 patients did the best. Stage 3 sort of did intermediate and stage 4 did the worst. This is what we would expect for a staging system. This is a staging system that works well. Now after 1995 and remember in this period we have the advent of a disease that switched from a tobacco and alcohol related disease to primarily one that is related to HPV and that HPV-associated oropharynx cancer does much better than HPVnegative oropharynx cancer. We can see that our staging system really doesn t work. Such that stage 3 patients shown here in green do the best, stage 4 in between and then stage 1 and 2 patients do the worst. Well I showed you previously that HPV-related oropharynx cancer patients tend to present with stage 4 disease and stage 3 disease and you can see, indeed, stage 3 and 4 did better than stage 1 and 2. And this was actually significantly so for stage 3 patients. So without the modern T and N staging system incorporating HPV, it s very difficult to provide prognostic information to patients merely on their staging of their tumor. Second point I wanted to make about prognosis in oropharynx cancer is that while the recurrence of this HPV-related cancer tend to be lower, less recurrence rates, the proportion of their recurrences the --- tend to be at distant sites --- distant metastatic sites is higher and that they --- when they do have distant metastatic disease, HPV-positive oropharynx cancer, it tends to be at multiple sites. So we can see here in the --- this upper table that local and regional recurrence rates are lower in the HPV-positive groups. This, again, comes from our colleagues at Toronto that local regional recurrences tend to be lower in HPV-positive than HPV-negative patients, quite a bit lower. This was significant. However, the proportion of the recurrences overall that were at distant sites was 44% of those in the HPV-positive group but only 27% in the HPV-negative group. And shown on this side, it shows that they tended to be multiple sites. Half of the distant recurrences happened at multiple sites --- excuse me --- half of the distant recurrences happened at multiple sites shown here as opposed to zero in the --- in the HPV-negative group. There were a quarter that had at two sites. Now, how about the timing of these distant metastases? This is another study --- followup study from the group in Toronto and it s not so evident here, but I just point you to two things on these curves. Classically head and neck cancer patients overwhelming recur if they re going to recur in the first two years. So this is the h --- HPV-negative side here. And you can see these curves which are detecting recurrence really flatten out after the two year point. In the HPV-positive curves, you can see these sort of drag out a little bit and distant metastases really are reported up to that 3 and even 4 year point in the --- in the HPV-positive group. So this point is we need to be careful about considering patients

5 disease-free at 2-year time interval. We really need to think about 3 and 4 and the classic 5-year time intervals you know maybe makes better sense. The other point about prognosis in --- in --- this has certainly been an issue for many years for head and neck cancer. But we want to talk about this specifically for HPV-related cancers of the oropharynx. Second primary cancers have always been a major problem for patients diagnosed with a head and neck cancer. And this curve shows by year and this is the excess risk for developing a second solid malignancy. And this is using the national database --- the SEER database. Oral cavity in blue is down here with one of the lower rates of second cancers. Larynx shown here in yellow, also a low rate of second cancers as compared to hypopharynx and oropharynx here. So back before the advent of the epidemic, the highest rates for second cancers were in oropharynx patients and hypopharynx patients, diseases that have traditionally been associated with very high consumption of tobacco and alcohol, as compos --- as compared to larynx and oral cavity cancer patients. And this is risk of second cancers at head and neck, lung, and esophageal sites. So classic tobacco-related sites and we can see, again, highest rates were in hypopharynx and oropharynx, lowest rates in larynx and oral cavity. And we can see --- after the advent of this HPV epidemic, we can see that now the second primary risk for orop --- oropharynx cancers is actually the lowest among the head and neck sites whether we look at any solid tumor or we look at head and neck and lung and esophagus, tobacco-related sites. This is some data from our institution showing that indeed patients whose tumors were HPV-positive had lower rates --- lower rates of second cancers compared to HPVnegative. So this is the proportion surviving free of a second cancer, HPV-positive having better second primary --- lower second primary rates than HPV-negative patients. And if we divided them by HPV-positive never smokers, HPV-positive smokers, and HPVnegative, we can see that our HPV-positive smoking group had second primary rates that were very similar to those who were HPV-negative. And that HPV-positive never smokers had very low rates of second cancers. We ve looked at this another way in a larger data set from MD Anderson, patients prospectively followed, treated at MD Anderson with oropharynx and non-oropharyngeal cancer. And you can see down here that --- at the time point zero, there were 1,000 patients --- over 1,000 patients with oropharynx cancer and almost 1,200 patients with non-oropharyngeal cancer. So that would be cancers of the larynx, the oral cavity, and the hypopharynx. And this is the proportion with a second cancer going up and up with time. And this is a very typical curve and increasing number of second cancers diagnosed in head and neck patients over time. And you can see at 5 years, this was in the 20% range. The oropharynx patients were quite a bit lower developing second cancers. And if we look at our population of oropharynx patients only, the second cancer rate was getting a little more similar to HPV-negative patients, patients with oral cavity cancer and larynx cancer if we looked at oropharynx but subtracted out those that we thought were likely HPV-positive. So males, age under 60, non-hispanic whites, never former smokers, small primaries, lots of lymph nodes with tonsil and base of tongue cancers. Those

6 patients had extremely low rates of second cancers as we might surmise from our HPVspecific work. Well secondly, while HPV-related oropharynx cancer and oropharynx cancers in general may have in the recent years a lower risk for second cancers, they may get these cancers at different sites. So typically tobacco-related head and neck cancer, the most common sites for second cancers tend to be the lung, other head and neck sites, the esophagus, and bladder, sites that tend to be related to tobacco exposure. So for HPV-related second cancers we might think of other HPV-related sites. So in this study we looked at the SEER registry and we looked at second --- risks for second cancers at --- in men at sites related to HPV. So in the top part of this graph, we see patients presenting with oropharyngeal index cancer meaning their first cancer was the oral or pharyngeal sites and their risk to develop second cancers of the anus or of the penis. And we can see that they had elevated risks to develop sites at these anogenital sites as opposed to sites that are not related to HPV. And similarly if we looked at patients who presented with an index cancer --- men who presented with an index cancer or first cancer at the anogenital sites their risk to develop second cancers of the tonsil or of the tongue base were elevated. And this was slightly more evident in men having never been married, shown with the circles, as opposed to men who were married. I want to touch on the concept of an HPV vi --- HPV-driven cancer versus simply an HPVassociated cancer. So please understand, you can find HPV in about 10-15% of men in their ---in their mouth and throat simply by testing a random group of men. So we want to know: is there evidence that the HPV we re detecting is actually driving that cancer. Now there s a suggestion of this in a large Phase III trial published by Ang et al., New England Journal of Medicine, And in that study they showed that HPV-negative patients, shown here in red, this is simply the recursive partitioning analysis which breaks patients up by their prognosis and resulted in these three different curves. Essentially the red group here is the HPV-negative group and the blue here tends to be the HPV-positive group, principally those with very limited tobacco exposure less than or equal to ten pack years or zero pack years. So that s a disease in which we don t really have another etiology. We don t have a smoking cause there and so we would think of this --- sort of the concept of this being an HPV-driven cancer. And then Dr. Ang and colleagues show that in the intermediate group, those with both tobacco exposure and being HPV-positive, they tended to have a survival somewhere in between. So they had risk associated with tobacco. In other words, the effects of tobacco on a cancer such as various mutations that are not commonly seen in HPV-related cancers, but also a cancer that has HPV as its cause or potential cause. A smaller study a little bit earlier showed that in patients who have an HPV-positive cancer in which the p53 protein is normal type of p53. In other words, a p53 that should have normal function. We can also think of that in a way that is an HPV-driven cancer. In other words, the p53 is not turned off by a mutation caused by tobacco. It s simply turned off by the E6 oncoprotein from HPV. As opposed to those who had HPV-positive cancers

7 with a mutant p53, the survival was much better. So the HPV-positive patient that had mutant p53 behaved more similar to the HPV-negative patient with p53 mutated. Another sign I showed you earlier of an HPV-driven cancer is p16 should naturally be overexpressed from the effect of E6 --- excuse me E7 on the Rb pathway. p16 should go up in its expression level. And similar to that previous slide showing p53 and HPV in conjunction, we see here that survival was much better for the HPV-positive if they were p16 overexpressors as opposed to the HPV-negative or the HPV-positive that does not overexpress p16. So this concept is that we have some other evidence that HPV is not just present but it s actually there and actually causing molecular changes that are associated with HPV oncoproteins driving that cancer. Finally, I want to touch on the clinical trials that are either shortly completed or have recently been completed and those that are recently opened at a national level. This is a study from ECOG. It s called It s a Phase II study. This is now recently closed and is in the period of followup and analysis. In that study, patients received induction chemotherapy, including paclitaxel, cisplatin, along with cetuximab. An evaluation for response at the primary tumor site was then performed. And those who had a complete response at the primary tumor irrespective of their response in the neck then went on to lower dose radiotherapy at 54 Gy with cetuximab versus those who had a partial response or stable disease at the primary site who went on to standard IMRT radiotherapy at 69 Gy, again with cetuximab. The concept of this trial is that if HPV patients --- patients with HPV-positive oropharynx cancer respond better to chemotherapy and in particular, the addition of cetuximab EGF-receptor targeted therapy, then you might offer those patients a lower dose of radiotherapy and thus less long term side effects and toxicity from their --- from their therapy. The national trial that s a Phase III trial, first Phase III trial devi --- designed specifically for HPV-positive oropharynx cancer is shown here. This is from the RTOG. It s called It s now completed accrual at 1,000 patients. And it randomized patients to two -- - essentially two standards of therapy for oropharyngeal cancer, IMRT with cisplatin versus IMRT with cetuximab. And the goal of this study is to determine really wit --- which is the better treatment for HPV-positive oropharynx cancer and also to look at some of the quality of life and functional outcomes that might be different between those receiving concurrent cisplatin versus those receiving concurrent cetuximab. They were also stratifying by smoking as we saw in th --- in the --- the previous RTOG study from --- published by Dr. Ang that smoking seems to be an important prognostic factor as well. Two trials which have just recently opened, that are important to talk about when we discuss oropharyngeal cancer are trials that are trying to incorporate robotic surgery and essentially transoral resection of these cancers into the treatment paradigm for these cancers. And the first one is the HPV po --- is designed for HPV-positive patients, patients with HPV-positive oropharyngeal cancer, that s the ECOG study, and then the RTOG study designed for patients with HPV-negative oropharyngeal cancer.

8 The ECOG study, this has probably accrued about 30 patients thus far nationally. It s a phase II-B design. It s called Patients undergo transoral asection --- transoral resection whether it s typical that this would be with robotic approach though some patients may undergo transoral resection with laser or other modalities. Low risk patients with negative margins go on to observation so they only have surgery avoiding radiotherapy. Patients with high risk features including positive margins more than 1 mm of extracapsular spread and five or more metastatic lymph nodes go on to concurrent postoperative dose radiotherapy with concurrent cisplatin. It s expected that the majority of patients will fall into the middle category of an intermediate risk, those with clear or close margins, those with less than 1 mm of extracapsular spread, those with two to four metastatic lymph nodes, those with perineural invasion or lymphovascular invasion. And they will be randomized to a lower dose of postoperative radiotherapy at 50 Gy versus a more standard dose of radio --- postoperative radiotherapy at 60 Gy. The study will look at outcomes of progression-free survival at two years and functional outcomes in quality of life as well. The goal for accrual is 377 patients. The RTOG study is a phase II-b design as well. It s designed for patients with oropharynx cancer that are HPV-negative. It s a very interesting design in that it s going to study the randomization for these patients to traditional standard treatment, chemotherapy and concurrent cisplatin --- excuse me --- radiation at 70 Gy with concurrent cisplatin compared to endoscopic head and neck surgery. Again, most of these will be done as transoral robotic surgery with adjuvant postoperative radiation therapy and concurrent chemotherapy as indicated by the pathologic findings. So at present we would say that we can sort of sum up what s available for patients with oropharynx cancer into the following. Patients with low risk cancers, those with HPVpositive in nonsmokers with lower nodal staging or perhaps no lymph nodes are treated with either radiation therapy alone as what would be the most common approach or transoral surgery in very selected patients. There will be the ECOG 3311 for HPV-positive patients available to these patients and there s a developing trial through RTOG called 1318 we didn t discuss. But this trial for low risk patients is being designed to treat patients with a lower dose of radiotherapy as the experimental approach for these with very low risk HPV-positive cancers. Patients with intermediate risk cancers, those that are HPV-positive typically with a smoking history or some of the staging criteria which increased their --- what we consider their risk for recurrence are treated with con --- standard treatment would be concurrent cisplatin and radiation therapy or in some cases concurrent cetuximab with radiotherapy. And for those patients some of them will be candidates for ECOG 3311 for the HPV-positive group. Other --- Ossu --- Others of them that are HPV-negative may be candidates for the RTOG HPV-negative study. And then there s a trial that will follow from RTOG for the --- for some of these HPV-positive patients as well such as For the high risk patients, those that are HPV-negative, those with very high stage --- nodal stage or even primary tumor site stage, most patients are also getting treated with concurrent treatment, cisplatin plus radiotherapy. There are induction trials available for selected patients. We p --- recently closed an in-house induction trial that finished accrual and I suspect there will be others available. And then RTOG has a trial 3501 which is available for HPV-negative patients with higher risk features.

9 So in summary, firstly we think about HPV-related cancer of the oropharynx as nowadays more of an HPV-driven cancer being those who either are never smokers, those with less smoking history, in other words a lower risk patient. From the research side, those tend to be patients that are with wild type p53 and those that have p16 overexpression. I didn t mention it, but our standard testing for oropharynx cancer now is both p16 immunohistochemistry which is a standard procedure done in virtually all pathology labs across the country. And we also do HPV in situ hybridization testing for high risk types to classify our patients as HPV-related or not. The staging system for oropharynx cancer I feel needs to be modified to incorporate HPV into the --- to the staging system as well as potentially smoking. Second primaries tend to be less of a problem in HPV-related oropharynx cancer than in traditional head and neck cancers, but these cancers at second primary sites may occur at these --- at different sites at HPV-related sites. Distant metastases is something we need to keep in mind in HPV-related cancer. They do occur. They do happen at somewhat odd sites in a little bit longer time from the end of treatment and often at multiple sites. So keep this in mind when following patients with HPV-related oropharynx cancer. And we need to be careful about the future and about selecting patients for intensification of therapy where appropriate and careful study of deintensification of therapy through clinical trials going forward. I cannot give a talk on HPVrelated oropharynx cancer without mentioning what we feel, and this is true for my colleagues not only in head and neck cancer, but also who deal with GYN-related cancers, pa --- my colleagues who deal with anal cancer, my colleagues who deal with penile cancers. These are preventable cancers and HPV vaccination should be recommended to all boys and girls in the age range appropriate, which at present is age 11 and that catch-up vaccination should be recommended for adolescents and young adults through age 26. We feel this is imperative to try to control this epidemic and to prevent many future people from suffering from these cancers and many --- excuse me and quite a bit of our national healthcare dollar being spent for the future treatment of these cancers. So with that I --- I m going to close and I would like to encourage you to please provide us with any feedback, ways that we might improve this lecture or any of our lectures related to HPV-related cancer. Thank you very much.