HPV-Positive Oropharyngeal Cancer: Maintain or De-Escalate Treatment?

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.

There now seems little doubt that clinical outcomes are much better for oropharyngeal cancers that are positive for human papillomavirus.

The question now, experts say, is what to do with that knowledge.

Current therapy for any head and neck cancer is arduous, to put it mildly, said Dr. Ezra Cohen of the University of Chicago. With its intense chemotherapy induction and wide-field radiation, "treatment for locally advanced head and neck cancer is really toxic," he said in an interview. "It’s about 6 months of very intensive treatment and recovery. Many patients require tube feeding and intravenous hydration. This leaves patients susceptible to infections and electrolyte imbalance, and – even though it’s sad to say – some small chance of mortality. It seems theoretically avoidable, but in truth about 1%-2% of patients will die because of treatment-related complications. We accept this, because most of these cancers will be cured, but it does come at a cost."

Patients with HPV-positive cancers may be in a better position to survive – mainly because their tumors seem more susceptible to treatment. But in the future, they also may be spared the intensive therapy that could, in fact, unnecessarily endanger them.

Several large epidemiologic and retrospective studies have confirmed the fact that HPV-positive oropharyngeal cancers are associated with better long-term outcomes than are HPV-negative tumors.

A 2007 analysis presented at the annual meeting of the American Society of Clinical Oncology found that HPV positivity conferred a 79% lower risk of death in the phase II ECOG (Eastern Cooperative Oncology Group) study of taxane-based induction chemotherapy followed by taxane-based concurrent chemoradiation in resectable stage III-IV larynx and oropharyngeal cancer patients.

More recently, investigators from DAHANCA (the Danish Head and Neck Cancer Group) reported that p16 expression – found in HPV-positive tumors – predicted better long-term outcomes for patients with oropharyngeal tumors in an analysis of data from two clinical trials. The analysis, presented at a meeting of the European Society for Therapeutic Radiation and Oncology, followed a pilot study that found p16 expression to be highly correlated with HPV infection in tissue from 32 tonsillar cancers.

These findings beg the question: Would HPV-positive tumors respond just as well to less-intense therapies, which could mean less danger for patients and certainly less discomfort and lower anxiety?

Two experts who were interviewed for this article agreed that more data are necessary to make an overall recommendation.

"This is a really exciting time in head and neck cancer," said Dr. Neil Hayes of the University of North Carolina at Chapel Hill. "We are on the verge of a transformation as to how we understand and treat these cancers, but are not quite there yet. With any major change in therapy or understanding of disease, there is a major transitional period in how we assess and treat it. With aggressive therapy, we are doing very well. We have not seen any large prospective studies that give us clear information that we can back off on the therapy."

Additionally, Dr. Hayes said, retrospective studies can all suffer from biases that slant the results, including potentially important risk factors like smoking. "It’s clear that smoking affects the risk in these tumors, but we don’t understand the biology of just how it does this. And partially because of this, it’s hard to say we really understand how HPV modifies the risk of the cancers, and how it does in relation to smoking."

There can be no question, however, that these decisions will need to be made, and soon. Epidemiologic studies from Scandinavia and Eastern Europe confirm that HPV-associated oropharyngeal cancer is rising at an alarming rate. "The data are real," Dr. Hayes said. "We are seeing a pandemic of HPV-associated tumors."

Again, the whys and wherefores remain unclear, said Dr. Cohen. "There has been a dramatic rise in our own country [and] in Canada, Scandinavia, and Western European countries over the past 3 decades. What’s really scary is, when you look at the curve, you can see that it is not flattening at all; it continues to rise more acutely, suggesting that we are at the beginning of this epidemic and it’s going to become even more common over the next decade or two."

Some researchers posit that the increase has a direct connection to a change in sexual practices – particularly an increase in oral sex, perhaps as people try to avoid other sexually transmitted diseases. "That’s not definitive, but it probably is true that sexual practices are changing during the last century. But there are some holes in that theory," Dr. Cohen said. "Data are emerging that there may be racial differences in HPV. Blacks seem to have a much lower incidence of the HPV-positive oropharyngeal tumors than whites. But the epidemiologic data don’t support the idea that there are differences in sexual practices. Again, there is so much we don’t know."

Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."

Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."

This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."

Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.

Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.

Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.

A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."

Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.

Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.

The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.

Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week

A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.

In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.

But caution should always be the watchword when data suggest a change in proven treatment, Dr. Hayes warned.

"As recently as a couple years ago, back-to-back publications supported induction chemotherapy plus chemo and radiation for head and neck cancer. A lot of this focus has now disappeared in the face of this HPV story. Three years ago, we were going for more and more aggressive therapy, and now we are talking about de-escalating therapy for these patients. I want to sound a warning: Two years ago we thought we understood this disease and [we increased treatment], and now we think we understand once more and want to decrease instead of increase treatment. We need a measured approach. It’s likely some patients may need more treatment, some need less, and some need different treatment. In the individual patients, we should consider all the data, but as a matter of policy, the data are not here yet."

Dr. Cohen and Dr. Hayes said they had no relevant financial disclosures.