HPV

Smell of a person’s breath may help identify early cancers

Source: www.theweek.in
Author: staff

Cancer researchers from Flinders University have reported significant progress in developing a method to test exhaled breath profiles which accurately differentiate head and neck cancer from non-cancer patients.

Previous studies elsewhere have indicated that the exhaled breath condensate can reveal gene mutations or DNA abnormalities in patients with lung cancer.

The global quest to use a person’s breath analysis for rapid, inexpensive and accurate early-stage testing for cancer and other diseases has taken a leap forward.

The Australian researchers collected breath samples from 181 patients suspected of having early-stage head and neck squamous cell carcinoma (HNSCC) before any treatment began.

“We sought to determine the diagnostic accuracy of breath analysis as a non-invasive test for detecting head and neck cancer, which in time may result in a simple method to improve treatment outcomes and patient morbidity,” says lead researchers Dr Roger Yazbek and Associate Professor Eng Ooi.

Worldwide, head and neck cancer accounts for 6 percent of all cancers, killing more than 300,000 people per year globally. Tobacco, alcohol and poor oral hygiene are known major risk factors for this cancer.

A surge in human papilloma virus (HPV)-associated head and neck cancers is seeing these cancers affecting a much younger population, the researchers say.

Current therapies are effective at treating early-stage disease, however late-stage presentations are common, and often associated with poor prognosis and high treatment-related morbidity.

In the Australian study, a selected ion flow-tube mass spectrometer was used to analyse breath for volatile organic compounds. Using statistical modelling, the Flinders researchers were able to develop a breath test that could differentiate cancer and control (benign disease) patients, with an average sensitivity and specificity of 85 percent.

Diagnosis was confirmed by analysis of tissue biopsies.

“With these strong results, we hope to trial the method in primary care settings, such as GP clinics, to further develop its use in early-stage screening for HNSCC in the community,” says co-lead author Dr Nuwan Dharmawardana.

The study has been published in the British Journal of Cancer.

October, 2020|Oral Cancer News|

Most parents of unvaccinated teens have no intention of getting HPV vaccine for their kids, study finds

Source: www.newstribune.com
Author: Kasra Zarei, The Philadelphia Inquirer

The human papillomavirus (HPV) vaccine has been proven to prevent certain types of oral and genital cancers and other health problems. However, in a study published this week in Lancet Public Health, researchers found that more than half of the parents of adolescents who have not received the HPV vaccine had no intention to initiate the vaccine series for their children.

Using data from a nationally representative survey of U.S. adolescents, the study authors estimated national-level and state-level parental intent to initiate and complete the HPV vaccine series for their kids. In states including Idaho, Montana, Nebraska, North Dakota, Oklahoma, and Utah, more than 65 percent of parents of unvaccinated adolescents had no intention to initiate the HPV vaccine series.

According to the most recent data by the Centers for Disease Control and Prevention, Wyoming and Mississippi have the lowest HPV vaccine rates at roughly 50 percent. The new study found of parents of unvaccinated adolescents in these states, almost 62 percent and 57 percent, respectively, did not intend to initiate the HPV vaccine for them.

Lack of parental intent to complete the vaccine series was lowest in the District of Columbia, at nearly 11 percent, and Rhode Island, at 20 percent. HPV vaccination is mandated in both regions.

In Philadelphia, HPV vaccine coverage is among the highest in the country — roughly 71 percent in 2018, according to CDC data. Still, in Pennsylvania, between 60-65 percent of the parents of unvaccinated adolescents do not intend to have their kids start the vaccine.

“I was surprised that the intent to vaccinate (for HPV) is this low,” said Cynthia DeMuth, a primary-care pediatrician in Harrisburg and the Pennsylvania chapter immunization representative for the American Academy of Pediatrics, who was not involved with the study.

The HPV vaccine guidelines recommend adolescents who start the vaccine series before their 15th birthday receive two doses, or three doses if they start after their 15th birthday.

But even among kids who receive the first dose, many parents don’t intend to have their child complete the series, the study found. Nationally, almost a quarter of the parents of adolescents who received the first dose of the vaccine had no intention to complete the series. In states like Arkansas, Florida, Georgia, Hawaii, Idaho, Utah, and West Virginia, that percentage was even higher at more than 30 percent.

Research suggests parents’ main driver is perceived safety of the vaccine, which may be due to past reports of adverse effects since the vaccine’s approval in 2006.

“It’s a safe and effective vaccine, and there haven’t been any serious adverse events related to the vaccine,” DeMuth said.

Studies have since proven rates of cancers that are prevented by the HPV vaccine have greatly decreased. Experts estimate widespread HPV vaccination has the potential to reduce new cervical cancer cases around the world by as much as 90 percent.

Lack of knowledge about the vaccine and lack of recommendations from health-care providers are also reasons expressed by parents with no intent to vaccinate their kids.

“Adults between the ages of 18 to 45 don’t even know what HPV is, and there is a vaccine to protect it,” said Kalyani Sonawane, professor in the department of management, policy, and community health at the University of Texas Health Science Center and lead author of the study.

There are also perceptions the vaccine is not needed for younger teens who may not be sexually active, as HPV is mainly sexually transmitted.

When declining the HPV vaccine, “sometimes parents say their child is too young and isn’t sexually active, and they’ll think about it for next year,” DeMuth said. “But the vaccine works better at young ages — the antibody levels are higher at a younger age with two shots compared to three shots at older ages.”

These trends worry experts who say it could cause a rise in HPV-related cancer rates.

“Particularly among girls, the coverage rate has not improved. If parents are not intending to vaccinate their kids, in the future, we could expect to see an increase in HPV-associated cancers,” Sonawane said.

Sonawane said while people may not think about HPV like measles, for which low vaccine coverage can lead to outbreaks, HPV is still an infectious disease and can remain in the body for years. HPV-related cancers are already on the rise by almost 3 percent. Experts caution if vaccine coverage doesn’t improve, increases in HPV-related cancers are only going to get worse.

Health care professionals and pediatricians can play an immediate role in addressing these potential health concerns.

“A strong recommendation from the provider is one of the most significant things providers can do,” DeMuth said. “The longer it’s been out, the more confident I am it’s safe, and the better I feel about giving a strong recommendation for the vaccine.”

August, 2020|Oral Cancer News|

Researchers take head and neck cancer by the throat

Source: www.brisbanetimes.com.au
Author: Stuart Layt

Research has identified more weak spots in a deadly type of head and neck cancer that it is hoped will lead to more effective treatments.

Oropharyngeal cancer can affect the base of the tongue, the tonsils, soft palate and parts of the throat, and almost half of all cases in Australia are caused by the human papillomavirus (HPV).

Current immunotherapies target two protein receptors on the cancer; however, they have had mixed success.

Lead researcher Professor Rajiv Khanna from QIMR Berghofer said they had identified four more spots on the genome of the cancer that they believed could be targeted by immunotherapy.

“Everybody has been trying to make immunotherapies that target those two antigens, but what we have found is that while those two are important, we were ignoring some of the other antigens,” Professor Khanna said.

“We took immune cells out of our patients and effectively asked them what they could “see” other than [the two proteins] E6 and E7, and actually they could see others.”

The study analysed immune cells taken from 66 oropharyngeal cancer patients at the Royal Brisbane and Women’s Hospital and the Princess Alexandra Hospital.

Co-lead author Professor Sandro Porceddu, the director of radiation oncology research at the Princess Alexandra Hospital, said they were now developing therapies based on the research.

“We’re already working on developing better killer T-cell immunotherapies that recognise all, or a combination, of these proteins,” Professor Porceddu said.

“Different combinations of the proteins are present on different patients’ cancer cells, so we will develop immunotherapies with different bunches of keys for different patients.”

At present, the cancer is treated with a combination of chemotherapy and radiation therapy, but it is hoped an effective immunotherapy will eventually become the standard treatment.

Oropharyngeal cancers are the sixth-most-common type of cancer worldwide, with US actor Michael Douglas diagnosed with stage four oral cancer in 2010, before going into remission after aggressive radiation treatment and chemotherapy.

Douglas credited HPV for his cancer but later said he was a heavy smoker and drinker, habits that also increase the risk of developing the disease.

In Queensland the incidence rate for the cancer type has increased by 162 per cent in men and 40 per cent in women over a 15-year period, according to data from the Cancer Alliance Queensland.

That is despite the development of the HPV vaccine from Professor Ian Frazer and his team at the University of Queensland in the early 2000s.

However, experts warn the impact of widespread immunisation programs for HPV will not be felt for decades.

The research has been published in the Journal of Experimental Medicine.

FDA approves Gardasil 9, the HPV vaccine, to prevent head-and-neck cancer

For the past decade, evidence has suggested that Gardasil, the HPV vaccine, could stem an epidemic of throat cancer. But it has also never received approval from the Food and Drug Administration for that use — and it was unclear if it ever would.

On Friday, the agency granted that approval, clearing the latest version of the vaccine, Gardasil 9, to prevent a cancer that affects 13,500 Americans annually. The decision was announced by Gardasil’s maker, Merck.

The decision doesn’t change recommendations about who should get the vaccine, which is already recommended for females and males ages 9 through 45 to prevent cervical, vulvar, vaginal, and anal cancer as well as genital warts. But cancers of the head and neck — mainly those of the tonsils and throat — have been left off the list.

It’s a striking omission, because head and neck cancer, mostly cancer of the throat, is the most common malignancy caused by HPV, the human papilloma virus, in the U.S. According to the Centers for Disease Control and Prevention, there are 35,000 cases of HPV-related cancer in the U.S. annually. On top of the 13,500 cases in the throat, 10,900 are cases of cervical cancer.

“That’s excellent news,” said Stewart Lyman, a pharmaceutical consultant whose doctors discovered a tumor in his throat in 2016. It was removed surgically, and was caused by HPV. “To have this extended to head and neck cancer is really very helpful for helping to inform the public that this serious disease, which has significant morbidity and mortality associated with it, can be prevented with the vaccine,” Lyman said.

Marshall Posner, the director of head and neck medical oncology at the Tisch Cancer Institute, said the approval is “a good thing for the FDA to do” and that he would be “thrilled” if head and neck cancer cases could be reduced through vaccination in coming decades. He said he has “every expectation” that an HPV vaccine would reduce cancer rates.

The original version of the Gardasil vaccine was approved in 2006 for girls and women between the ages of 9 and 26 based on data from clinical trials showing that the vaccine, by preventing HPV infection, could also prevent precancerous cervical lesions. But such lesions don’t exist in head and neck cancer, and it was not clear how to prove the vaccine’s efficacy.

Maura Gillison, now a professor at M.D. Anderson Cancer Center, first connected a subset of head-and-neck cancers to HPV in 1999. But then she and other epidemiologists noticed something: The number of head and neck cancers was rising rapidly, and HPV seemed to be a culprit. What’s more, these sexually transmitted cases seemed different — and somewhat easier to treat. The most common victims were middle-aged men who had contracted the virus decades before.

The FDA is granting what’s known as an accelerated approval, meaning that the decision is contingent on the production of more data and is based on what’s known as a “surrogate endpoint” — an indication that a medicine works that is not foolproof. In this case, the FDA is approving the drug based on data on preventing anogenital infection. In February, Merck began a study of  6,000 men that will test whether patients who receive the vaccine are less likely to get persistent HPV infections in their throats.

Adding another disease to the approval does impact what Merck can say to doctors and patients about HPV and head and neck cancer. “It’s something that was missing in the label,” said Alain Luxembourg, director, clinical research, Merck Research Laboratories. “It is something missing in the conversation between patients and doctors.”

Otis Brawley, an oncology and epidemiology professor at Johns Hopkins University, said that while he is usually opposed to surrogate endpoints, in this case he is comfortable with the decision. “There’s already enough reasons to vaccinate for HPV in men,” he said, adding that doing so broadly might make it possible to eradicate the virus, and the cancers it causes.

For Gillison, who spotted the emergence of HPV throat cancer, it came too late. She pushed Merck to do a study, and said that the one that started in February is coming “10 years plus after when it would have really mattered.” She also thinks that the real reason for the decision is the weight of epidemiologic evidence that she and others produced.

“The fact of the matter is that this approval probably has little whatsoever to do with the anal data per se,” Gillison wrote via text message. “It is because the FDA is made more comfortable with inference because of all the data that has been generated regarding the relationship between oral HPV infection and HPV vaccination outside of vaccine trials in the last 10 years.”

June, 2020|Oral Cancer News|

FDA approves Gardasil 9, the HPV vaccine, to prevent head-and-neck cancer

Source: www.statnews.com
Author: Matthew Herper

For the past decade, evidence has suggested that Gardasil, the HPV vaccine, could stem an epidemic of throat cancer. But it has also never received approval from the Food and Drug Administration for that use — and it was unclear if it ever would.

Charles Rex Arbogast/AP

On Friday, the agency granted that approval, clearing the latest version of the vaccine, Gardasil 9, to prevent a cancer that affects 13,500 Americans annually. The decision was announced by Gardasil’s maker, Merck.

The decision doesn’t change recommendations about who should get the vaccine, which is already recommended for females and males ages 9 through 45 to prevent cervical, vulvar, vaginal, and anal cancer as well as genital warts. But cancers of the head and neck — mainly those of the tonsils and throat — have been left off the list.

It’s a striking omission, because head and neck cancer, mostly cancer of the throat, is the most common malignancy caused by HPV, the human papilloma virus, in the U.S. According to the Centers for Disease Control and Prevention, there are 35,000 cases of HPV-related cancer in the U.S. annually. On top of the 13,500 cases in the throat, 10,900 are cases of cervical cancer.

“That’s excellent news,” said Stewart Lyman, a pharmaceutical consultant whose doctors discovered a tumor in his throat in 2016. It was removed surgically, and was caused by HPV. “To have this extended to head and neck cancer is really very helpful for helping to inform the public that this serious disease, which has significant morbidity and mortality associated with it, can be prevented with the vaccine,” Lyman said.

Marshall Posner, the director of head and neck medical oncology at the Tisch Cancer Institute, said the approval is “a good thing for the FDA to do” and that he would be “thrilled” if head and neck cancer cases could be reduced through vaccination in coming decades. He said he has “every expectation” that an HPV vaccine would reduce cancer rates.

The original version of the Gardasil vaccine was approved in 2006 for girls and women between the ages of 9 and 26 based on data from clinical trials showing that the vaccine, by preventing HPV infection, could also prevent precancerous cervical lesions. But such lesions don’t exist in head and neck cancer, and it was not clear how to prove the vaccine’s efficacy.

Maura Gillison, now a professor at M.D. Anderson Cancer Center, first connected a subset of head-and-neck cancers to HPV in 1999. But then she and other epidemiologists noticed something: The number of head and neck cancers was rising rapidly, and HPV seemed to be a culprit. What’s more, these sexually transmitted cases seemed different — and somewhat easier to treat. The most common victims were middle-aged men who had contracted the virus decades before.

The FDA is granting what’s known as an accelerated approval, meaning that the decision is contingent on the production of more data and is based on what’s known as a “surrogate endpoint” — an indication that a medicine works that is not foolproof. In this case, the FDA is approving the drug based on data on preventing anogenital infection. In February, Merck began a study of 6,000 men that will test whether patients who receive the vaccine are less likely to get persistent HPV infections in their throats.

Adding another disease to the approval does impact what Merck can say to doctors and patients about HPV and head and neck cancer. “It’s something that was missing in the label,” said Alain Luxembourg, director, clinical research, Merck Research Laboratories. “It is something missing in the conversation between patients and doctors.”

Otis Brawley, an oncology and epidemiology professor at Johns Hopkins University, said that while he is usually opposed to surrogate endpoints, in this case he is comfortable with the decision. “There’s already enough reasons to vaccinate for HPV in men,” he said, adding that doing so broadly might make it possible to eradicate the virus, and the cancers it causes.

For Gillison, who spotted the emergence of HPV throat cancer, it came too late. She pushed Merck to do a study, and said that the one that started in February is coming “10 years plus after when it would have really mattered.” She also thinks that the real reason for the decision is the weight of epidemiologic evidence that she and others produced.

“The fact of the matter is that this approval probably has little whatsoever to do with the anal data per se,” Gillison wrote via text message. “It is because the FDA is made more comfortable with inference because of all the data that has been generated regarding the relationship between oral HPV infection and HPV vaccination outside of vaccine trials in the last 10 years.”

Fighting throat cancer with T cells

Source: www.miragenews.com
Author: press release, Centenary Institute

Research led by the Centenary Institute has discovered that immune cells accumulating within the tumor environment, called tumor-resident T cells, are a critical determinant in survival rates of patients suffering from throat cancer.

Reported in the prestigious ‘Journal for ImmunoTherapy of Cancer’, the research suggests that strategies aiming to boost these T-cells at tumor sites could be beneficial to patients.

“Oropharyngeal squamous cell carcinoma (OPSCC) is a form of throat cancer. It can be caused by environmental factors such as smoking or by human papillomavirus infection (HPV), the same virus that causes cervical cancer in women,” said Ms Rehana Hewavisenti, lead author of the study and researcher at the Centenary Institute and the University of Sydney.

“We knew that patients with HPV-related OPSCC had far better clinical outcomes compared to other OPSCC patients but we didn’t know why,” she said.

In examining over sixty patient samples, Ms Hewavisenti and her colleagues discovered that increased levels of tumor-resident T cells, whether in HPV or non-HPV OPSCC cases, was clearly associated with improved patient survival outcomes.

“It was the accumulation of these immune T-cells, in and around the tumour site that appeared to be key,” said Ms Hewavisenti.

The researchers also found in their study that HPV OPSCC patients generally had far higher levels of tumour-resident T cells compared to their non-HPV OPSCC patient counterparts.

“We think these HPV positive patients tended to have better clinical outcomes as HPV infection is likely to favor the accumulation of these beneficial T-cells within the tumor area,” she said.

Dr Mainthan Palendira, Head of the Centenary Institute’s Human Viral and Cancer Immunology Laboratory and senior author on the research paper believes the research findings have major implications.

“Now that we understand how important this immune response is in relation to OPSCC, we can begin developing new treatment strategies focused on recruiting these favourable tumor-resident T cells directly to tumors,” he said.

Dr Palendira believes that looking at the amount of these T-cells in cancer could help clinicians to personalize the best treatment approach for individual patients.

“We also think that our research demonstrating viral (HPV) links with this tumor-resident T cell accumulation could help in future cancer vaccine development efforts too,” he said.

Experts release new guidelines for studies into most effective treatments for HPV-positive throat cancer

Source: en.brinkwire.com
Author: provided by University of Birmingham, United Kingdom

Heightened caution is needed when considering de-escalation trials for patients with Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), to ensure minimal harm to patients, new guidelines from a group of international head and neck cancer experts have suggested.

HPV-positive oropharyngeal cancer is a cancer of the throat caused by the human papillomavirus—a common, but symptomless group of sexually transmitted viruses. Instances of many throat and neck cancers have declined as smoking rates have fallen, whereas HPV-positive OPC has increased, largely affecting younger patients.

The standard course of treatment for this disease is a combination of cisplatin (a common chemotherapy drug) and radiotherapy. The younger age of the patient population, significantly improved prognosis, and relatively minimal morbidities caused by the standard treatment pathway have led to the popularisation of the concept of treatment de-escalation as a way to improve the quality of life of patients by reducing dosage or frequency of treatment.

These new recommendations, published today in the Journal of Clinical Oncology have been created by the Head and Neck Cancer International Group, a group of experts from nineteen countries, led by the University of Birmingham, UK. The guidelines have been prompted by the recent results of the first three randomised de-escalation trials which suggested a clear detriment in survival when cisplatin is omitted or substituted to minimise side effects.

After a review of available HPV-positive OPC literature, the guidelines recommend an overall need for caution when considering de-escalation options, even in instances where there appears to be possible favourable disease outcomes. Experts also recommend a revised approach to how findings are evaluated during phase II studies to ensure that any potential risks to survival are identified and only if none are present should phase III trials follow.

The guidelines also recommend that de-escalation trials should only be considered for well-defined, very low risk groups and only when there is a strong rationale for investigating a particular treatment strategy. Additionally harm-minimisation techniques should be considered as an alternative. Importantly, treatments should not be implemented into clinical practice before high level evidence is available.

Corresponding author Professor Hisham Mehanna, Director, Institute of Head and Neck Studies and Education (InHANSE) at the University of Birmingham said: “Clinicians and researchers have to be careful when planning and undertaking de-escalation studies, as trials to date have that harm can befall patient. Very controlled and small strides need to be taken when evaluating a possible de-escalation strategy, especially one that removes cisplatin.”

Less intense treatment safe for HPV+ throat cancer

Source: www.miragenews.com
Author: public release, University of Pittsburgh School of Medicine

A less intense treatment for human papillomavirus positive (HPV+) throat cancer—using robotic surgery followed by low-dose radiation—could provide as much benefit as standard higher-dose radiation and chemotherapy while preserving a patient’s throat function, and with potentially less toxicities, according to researchers at UPMC Hillman Cancer Center and Yale Cancer Center.

The results of their randomized phase two clinical trial will be presented virtually this week at the American Society of Clinical Oncology (ASCO) annual meeting during the Head and Neck Oral Abstract Session (Abstract 6500).

“These results present a promising deintensification approach that has proven to be safe in patients with intermediate risk, locally advanced oropharynx cancer,” said Robert Ferris, M.D., Ph.D., director, UPMC Hillman Cancer Center and a surgical oncologist specializing in head and neck cancer, who was lead investigator of the trial. The results are not yet published in a peer-reviewed journal.

About 60% of oropharynx cancer, in which cancer cells form in the back of the throat, base of the tongue and tonsils, is associated with HPV infection. The incidence has been increasing in recent years, especially in individuals under the age of 45.

Following robotic surgery, patients with HPV-associated throat cancer would typically undergo high dose radiation and chemotherapy. While robotic surgery allows for more precise and optimal preservation of the organs and surrounding tissue, there is still concern with the toxicities from the chemotherapy and consequences of tissue damage from radiation therapy, particularly in a younger population.

“Most throat cancers caused by HPV have good outcomes, and the cancer doesn’t return or spread to other parts of the body after treatment,” said Ferris, who also is professor, Department of Otolaryngology, of Immunology, and of Radiation Oncology, University of Pittsburgh School of Medicine.

“In this trial, we studied the pathologic features of the tumors obtained at surgery to determine patients’ risk of recurrence—low, intermediate or high—to then administer the right amount of postoperative treatment for each risk group.”

Patients at low risk were observed. Patients at intermediate risk were randomized to two arms of radiation alone, at standard or lower doses of radiation. Patients at high risk were assigned to usual high-dose radiation therapy plus chemotherapy.

For patients at low and intermediate risk, the two-year, progression-free survival rate was approximately 95%, and reducing radiation or chemotherapy intensity did not increase the risk of recurrence.

“The tissue samples and imaging studies collected in the course of this trial are a rich resource for studying the biology of intermediate- and high-risk disease, in work that is ongoing,” said ECOG-ACRIN Head and Neck Committee Chair Barbara Burtness, M.D., professor of medicine, and co-leader, Developmental Therapeutics Program, Yale Cancer Center and Yale School of Medicine.

Note:
The ECOG-ACRIN Cancer Research Group designed and conducted the trial with funding from the National Cancer Institute, part of the National Institutes of Health.

Deintensification of Treatment in HPV-Associated Cancers Holds Promise, But With Caveats

Source: Targeted Oncology
Date: May 17th, 2020
Author: Tony Berberabe

 

De-escalating therapy has the potential to dramatically reshape the treatment of patients with HPV-associated oropharyngeal cancers, but only if a number of key trials come back with positive long-term data with 3 cycles of cisplatin at 100 mg/m2 times 3, given every 3 weeks, Sue Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology-Head and Neck Surgery atthe University of California, San Francisco, said in an interview with Targeted Therapies in Oncology (TTO).

Sure, there were some minor variations over the years, small alterations made on a case-by-case basis. “But long story short, that’s fundamentally what was happening: 70 Gy with 3 cycles of high-dose cisplatin,” Yom said. The story began to change a little over a decade ago, with the introduction of a variable that could potentially change the course of therapy for a large percentage of patients with head and neck cancers. Today, the operative word remains potentially.

In 2008, Maura L. Gillison, MD, PhD, of Johns Hopkins University, and colleagues found that whether head and neck squamous cell carcinoma tumors were associated with the human papillomavirus (HPV) turned out to be a major prognostic indicator.1

“When that finally came to be reported, there was a very, very striking result,” said Barbara Burtness, MD, a professor of medicine (medical oncology), Disease-Aligned Research Team leader of the Head and Neck Cancers Program, and coleader of Developmental Therapeutics at Yale Cancer Center in New Haven, Connecticut Patients with HPV-associated stage III or IV head and neck squamous cell carcinoma of the oropharynx or larynx had a 2-year overall survival (OS) rate of 95% versus 62% for patients with HPV-negative tumors.

Two years later, Gillison collaborated with K. Kian Ang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston and published the results of a study in oropharyngeal cancer (NCT00047008), which again found that HPV made a difference in terms of survival.2

Patients with HPV-positive tumors had better OS and progression-free survival (PFS) than patients who were HPV negative (P<.001 for both comparisons). Ang and colleagues reported that the 3-year OS rate was 82.4% (95% CI, 77.2%-87.6%) in patients who were HPV positive compared with 57.1% (95% CI, 48.1%-66.1%) in those who were HPV negative. Similarly, the 3-year PFS rate favored the HPV-positive group, at 73.7% (95% CI, 67.7%-79.8%) versus 43.4% (95% CI, 34.4%-52.4%) for the HPV-negative group (TABLE 1).2

The 3-year absolute benefit of HPV-positive status for OS was 25% (95% CI, 11%-40%), and the absolute benefit for PFS was 30% (95% CI, 15%-45%).

The results were similar with stratification according to p16 expression status. The 3-year rates of OS were 83.6% (95%CI,78.7%-88.6%) in the subgroup that was positive for p16 expression and 51.3% (95% CI, 41.5%-61.0%) in the subgroup that was negative (P<.001). Three-year PFS rates were 74.4% (95% CI, 68.5%-80.2%) and 38.4% (95% CI, 28.9%-47.9%), respectively (P<.001) (TABLE 2).

The study also found that the number of pack-years an individual smoked had a substantialnegative impact on prognosis.

These findings raised serious questions because the current standard of care, unchanged from that described by Yom, can have a profound effect on the life of a patient who survives the cancer. “The after- effects of that dose of radiation are quite real, and they include chronic pain, chronic swallowing difficulties, dry mouth, and dental complications,” Burtness said.

“We are concerned that these patients may be at higher risk for death from the late effects of the treatment.”

Moreover, patients with HPV-associated cancers tended to be younger at diagnosis than those with non-HPV cancers. Patients who develop the cancer in their 50s might have decades of life left—plenty of time for the long-term adverse effects (AEs) of aggressive treatment to show up.

The issue is pressing because HPV-associated cancers represent about 7 in 10 cases of oropharyngeal cancer.3 The most recent statistics from the Centers for Diseases Control & Prevention suggests that 3500 new cases of HPV-associated oropharyngeal cancers are diagnosed in women versus 15,500 diagnosed in men (FIGURE 1).4

Cherie-Ann O. Nathan, MD, chairman of the Department of Otolaryngology–Head and Neck Surgeryat Louisiana State University Health Shreveport, said the new findings underscored the need for more research. “We need to start to look at de-escalating for that low-risk group,” she said.

De-escalation Strategies

Deciding that different strategies might be warranted and choosingwhich approaches make the most sense are 2 different considerations, and both come with difficult questions. Burtness said it can be a challenge just to figure out how to tackle the question.

I think, first of all, it’s challenging to do deintensification trials because they require very large sample sizes, and you want to be sure you’re not deintensifying [treatment in] somebody who would be cured by the full treatment and wouldn’t be cured by the reduced regimen,” Burtness said.

For the most fortunate patients, the OS rate with the current standard of care is in the range of 90% to 95%, setting a high bar for its replacement, Yom said. “It’s a huge ethical and practical situation where you’re actually having to estimate: ‘What would it take to prove that this less intense alternative was as good?’” Yom said.

“Patients do get better with time,” Yom said. “After a year or 2, they can live very normal lives.It’s actually a great treatment in some ways, and 1 question is if we should even be messing with it.”

Another strategy is to reduce the dose or field of radiation. In Yom’s much-anticipated trial, NRG-HN002 (NCT02254278), 306 patients with p16-positive, non–smoking-associated, locoregionally advanced oropharyngeal cancer were stratified by unilateral or bilateral radiation and randomized into 2 groups.4 One group received 60 Gy of intensity-modulated radiation therapy (IMRT) for 6 weeks plus cisplatin (IMRT + C) at 40 mg/m2 weekly. The other group received 60 Gy of modestly accelerated IMRT alone for 5 weeks. The goal was to compare the arms in terms of 2-year PFS rates without unacceptable swallowing difficulty at 1 year. The IMRT + C group met the desired benchmarks; the IMRT alone group did not.

Although the study was just a phase II trial, Yom said the results were encouraging and will lead to further study.

Another strategy is to perform surgery up front, Nathan said. If the margins are negative and there is not a significant number of metastatic lymph nodes or significant extranodal extension, chemotherapy might be avoided. She said transoral surgery has become much more effective and precise in the age of robotics. A common site of lymph node involvement is the retropharyngeal region, shown in FIGURE 2.5

“When robotic surgery became popular and we were able to get margins on these tumors at the base of [the] tongue and tonsils, people started saying [that] for the HPV-associated [tumors], you don’t need the typical wide margins of 5 mm; you could get away with 3 mm,” she said.“ So, the whole purpose of transoral surgery was that after removing the tumor, you could de-escalate.”

Other research has tested the replacement of cisplatin with cetuximab (Erbitux), though one study found that the latter resulted in inferior OS.6

With the exception of the cetuximab strategy, the novel approaches have shown promise. However, Nathan said, clinicians should realize that these are all still hypotheses; there is much that is not yet known.

“Unfortunately, people look at all [these] retrospective data and small institutional trials and make [treatment] decisions, not realizing that it’s still not standard of care,” Nathan said. “It’s fine to de-escalate, but always de-escalate if you can on a clinical trial.”

Ongoing Research

A number of important ongoing trials have the potential to add significant scientific rigor to the debate. Among them is Eastern Cooperative Oncology Group’s ECOG-E3311 trial (NCT01898494), which is examining transoral surgery followed by low- or standard-dose radiation therapy with or without chemotherapy. Initial findings are expected to be presented at the 2020 American Society of Clinical Oncology Annual Meeting and the trial is expected to be completed in 2023. The PATHOS trial (NCT02215265), which is evaluating transoral resection followed by reduced-intensity radiotherapy with or without cisplatin, is expected to be completed in 2026.

Yom and colleagues are working on NRGHN005 (NCT03952585), a phase II/III study in which patients will undergo deintensified radiation therapy with cisplatin or the PD-1 inhibitor nivolumab (Opdivo) versus standard-of-care chemoradiation. The investigators used an innovative design so that the study will produce scientifically rigorous results for the 70 Gy versus 60 Gy question at the phase III level, even if the nivolumab phase II investigation does not meet its targeted end points, Yom told TTO.

In the meantime, Burtness said, the data are beginning tosuggest, if not conclusively, which types of patients might be a good fit for deintensification. “The omission of chemotherapyin the postoperative setting after transoral resection is probably better for patients with smaller nodes, maybe only 1 or 2 nodes,” she said. “The use of more induction chemotherapy and a lesser dose of radiation is better, obviously,for patients who are going to tolerate chemotherapy well. The omission of systemic chemotherapy and the use of immunotherapy may eventually [lead to the development of] a biomarker signature.”

She cautioned that it is not clear that all HPV-associated cancers should be treated the same way. Certain other factors appear to affect the opportunity for deintensification. “Repeatedly, we’ve seen [that] patients with T4 cancers don’t do well with deintensification,” she said. “Patients who’ve smoked more than 10 pack-years won’t do well.”

Burtness added that there is a good chance the end result of all the research will simply be that certain deintensification strategies are better for certain patient populations. Yom agreed. “One of our goals is to make deintensification acceptable within the standard of care,” she said. “But I’m not sure there’s going to be just 1 standard of care going forward.”

Even if these new strategies show equal or better success rates compared with the current standard ofcare, patients who undergo deintensified therapy might avoid the toxicities of more intense therapy at the cost of unexpected long-term AEs.

The 2 key takeaways from the study we put together are that, 1, there are a lot of different deintensification strategies, and in the short term, a lot of these different strategies don’t show any differences in outcomes or toxicity,” Patel said. “But the second point that is crucial is that longer-term follow-up is necessary for making judgments as to whether or not to do deintensified treatments.”

Nathan said 1 major concern is that patients with deintensified treatment regimens might facea higher risk of a subsequent cancer diagnosis. “HPV- associated cancers still have the same distant metastasis rate as HPV-negative cancers,” she said. “And the distant metastasis is occurring years later and sometimes in unusual locations.”

For example, lack of systemic therapy might not affect the current oropharyngeal tumor, but years later, could it lead to a cancer that might have been prevented? That type of question is impossible to answer at thispoint, andNathan says it is problematic to assume the answer is no.

Nathan also raised concerns about changes to the American Joint Commission on Cancer (AJCC) staging system. In the eighth edition of the AJCC Cancer Staging Manual, HPV-associated cancers were restaged because staging is generally meant to match prognoses, and HPV-associated cancers had been shown to have better prognoses, she said.The end result of the restaging, she said, is that some cancers previously deemed stage IV might now be reclassified as stage I or II. Nathan worries that the lower staging will result in even more deintensification because clinicians will not consider cases as serious as they once did, which would be a mistake, she said. “All the patients who did so well and have such good survival [in the existing de-escalation literature] were being treated like they were stage III or IV,” she said. “So, until you have the results of [ongoing clinical trials], you shouldn’t be doing it.”

Deintensification Today

Clearly, some level of deintensification is occurring withinclinics inthe United States.If itturnsout that 1 or more of the new, lower-intensity strategies is effective, the treatment paradigm for patients will be drastically different, Yom said:“To start talking about things like patient preferences and quality of life is foreign and different in oropharyngeal cancer.”

Patient preference is a key consideration,Patel said: “That’s why the data and being able to share with patients that these outcomes aren’t different at longer-term follow-ups is important.”

Different types of patients will likely favor different approaches, even if de-escalation is validated as a standard option, according to Yom. “I have patients who come to my clinic, and they’re like, ‘I have 2 kids. I’m staying alive. Hit me with everything you have,’” she said.

A large spectrum of Yom’s patient population is very highly educated about their cancers, she said, and that knowledge can inform the strategies they prefer. In many cases, education leads patients to be less concerned about mortality and more concerned about the impact of therapy on quality of life.

“There’s a large proportion of that population where their driving concern is this fear of long-term consequences,” she said.

Yom said radiation oncologists will need to better help patients, who until now had few treatment choices, think through their options. “We don’t have good structures and instruments to help people sort through the decision-making process ina way that makes sense to them,” she said. “I don’t think anybody does.”

Even if the data from the current trialsare positive, Nathan cautioned, the time horizon to evaluate outcomes must be longer than a few years. “Most of these trials are looking good, but follow-up is only about 3 to 4 years, she said. “A lot of our toxicities [that we have seen] have occurred 5 and 8 years later.”

That will require oncologists to be involved in decisions that might be thornier than those patients previously faced. “You’re going to have to be a much better oncologist,” Yom said.

Still, she and others say the challenge will be well worth it, but only if the ongoing scientific study findings support the optimism now shared by many in the field. “This deintensification movement will have huge implications [for] how the majority of patients with head and neck cancers will be treated in this country going forward,” Yom said.

May, 2020|Oral Cancer News|

An Occult HPV-Driven Oropharyngeal Squamous Cell Carcinoma Discovered Through a Saliva Test

Source: Frontiers in Oncology
Date: March 31st, 2020
Authors: Kai Dun Tang, Sarju Vasani, Touraj Taheri, Laurence J. Walsh, Brett G. M. Hughes, Lizbeth Kenny, and Chamindie Punyadeera

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Introduction

The incidence of high-risk human papillomavirus (HR-HPV−16,-18,-33) driven oropharyngeal cancer (OPC) is rapidly increasing in developed countries (13). HPV-driven OPCs have surpassed cervical cancer as the most common HPV-driven cancer in the USA. The prevalence of HR-HPV has been reported as 3.7% of the USA population, with a bimodal age distribution of incidence (4). It remains unclear why some individuals go on to develop OPC, while others clear the initial HPV infection (5). The strong association between HR-HPV infection and cervical cancer has led to screening programmes in primary healthcare settings, resulting in earlier diagnosis and a reduction in cancer deaths (6). Unlike cervical cancer, no screening test is available for OPC and current HPV vaccines have yet to demonstrate any reduction in future OPC development (7). Here, we report the first ever case of occult OPC detected as a direct result of a theoretical screening test—in this case HPV-16 DNA analysis in salivary oral rinse samples. Our clinical and pathological findings increase our understanding of both the natural history of the disease and the potential for wider screening to identify early stage OPC, facilitating less morbid treatments.

Cases Presentation

An ongoing HPV-16 DNA prevalence study was approved by institutional ethics committees from the University of Queensland; Queensland University of Technology and the Royal Brisbane and Women’s Hospital. A total of 665 cancer-free healthy individuals from Queensland Region, Australia between May 2016 and October 2017 were recruited. All participants gave written informed consent prior to sample collection.

Six hundred and fifty cancer-free healthy individuals with sufficient amount of DNA were tested for oral HPV-16 DNA. Of these 3 have been identified to have persistent oral HPV-16 DNA infection. Following discussion with our ethics team we have approached these three participants and offered them consultation with an Ear, Nose, and Throat (ENT) surgeon. A 63-year-old caucasian male was assessed as part of this consultation process. He had consistently been HPV-16 DNA positive for a period of 36 months, with a steadily rising HPV-16 viral load in his salivary oral rinse samples (Figure 1A). He was invited to attend the ENT clinic for assessment and discussion.

FIGURE 1
www.frontiersin.orgFigure 1. Occult oropharyngeal microcarcinoma detected based on a screening test through the serial measurements of salivary HPV-16 DNA. (A) HPV-16 DNA viral load in salivary oral rinse samples over time. B (Baseline); F1 (6 month follow-up); F2 (12 month follow-up); F3 (36 month follow-up); PT (2-week post-tonsillectomy). (B) Sections of the left tonsillar tissue found a 2 mm non-keratinising squamous cell carcinoma, with focal stromal invasion <1 mm, excised with clear margins. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Hematoxylin-eosin (H&E x200) (C) HPV-16 DNA was only positive in left tonsillar tissue. (D) p16INK4a immunohistochemistry staining (IHC) x20: Diffuse positive brown staining for p16INK4a in tumor region comparing non-affected area in the left tonsil.

He is an ex-smoker, having quit 15 years ago, with a 45 pack year history of smoking. He drinks two standard drinks (2.5 units of alcohol) per day. He is heterosexual, and his social history includes multiple oral sex partners in the past (>5), followed by a long term monogamous relationship. Initial clinical examination of the oropharynx including palpation and white light revealed no significant abnormalities. Both tonsils were irregular due to mucous retention cysts and there was slight tonsillar asymmetry (Left < Right) but no evidence of any malignant lesions. Narrow band imaging (NBI) showed some mild vascular changes at the left glosso-tonsillar sulcus. There were no palpable lymph nodes in the neck. An MRI examination of the oropharynx and neck demonstrated no occult lesions of the tonsils or the base of tongue and no cervical lymphadenopathy.

He was offered continued surveillance, or a biopsy of the area of NBI change with bilateral tonsillectomy. The patient elected for bilateral tonsillectomy and biopsy of the base of tongue with NBI guidance under general anesthetic and informed consent was obtained. The surgical specimens were sent for histology and tissue HPV-16 DNA testing. The patient was discharged from hospital the same day. He had a routine postoperative course with a sore throat for 1 week and recovered fully. An ultrasound scan of his neck was performed 2 months post-surgery which showed no cervical lymphadenopathy. He is currently under routine oncological surveillance. The patient has a very high likelihood of cure with minimal morbidity from single modality treatment.

Clinical Specimens’ Collection and Processing

Salivary oral rinse samples of this individual were collected at baseline, 6, 12, 36 month, and 2 weeks after his bilateral tonsillectomy using previously published method (810). Briefly, participants were asked to swish and gargle for 1–2 min with 2 × 10 mL volumes of 0.9% saline, prior to expectorating the rinse sample into a 50 mL falcon tube. Tissue biopsies from the tonsil and base of tongue were obtained after surgical resection. All samples were immediately frozen on dry ice upon collection and transported back to the laboratory for subsequent processing.

HPV-16 DNA QPCR Analysis

Total DNA was extracted from salivary oral rinse and tonsillar tissue samples using the QIAmp DNA Mini Kit (Qiagen, Germantown, MD, USA) as per manufacturer’s protocol. For detection of HPV-16 genotyping, the qPCR assay targeting the opening reading frame (ORF) region of HPV16 E6/7 was carried out with the QuantStudio™ 7 Flex Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) as described previously (11, 12). For quantification of HPV-16 DNA viral copies in salivary oral rinse and tissue samples, a standard calibration curve was generated using qPCR by plotting threshold cycle (Ct values) against the logarithm of the copy number of 8-fold serially diluted (1 × 101-1 × 108 copies) of pHPV-16 plasmid DNA [American Type Culture Collection (ATCC)® 45113™].

Immunohistochemistry

H&E (Haemotoxylin and Eosin stains) staining on formalin-fixed paraffin-embedded (FFPE) slide was performed to investigate the cellular and tissue structure/morphology. HPV status was evaluated using CINtec® p16INK4a Histology Kit (E6H4 clone) (Roche MTM Laboratories, Heidelberg, Germany) according to manufacturer’s instructions. p16INK4a was considered positive by two independent pathologists when there was a strong, diffuse nuclear and cytoplasmic staining pattern in the majority (>70%) of tumor cells.

Salivary HPV-16 DNA as a Biomarker-Based Tool for HPV-Driven OPC Screening

Salivary oral rinse samples from this individual had been collected at baseline, 6, 12, and 36 month follow-up as well as 2 weeks after his bilateral tonsillectomy. HPV-16 DNA genotyping and viral loads in all samples were analyzed using an in-house developed qPCR assay. HPV-16 DNA viral load in saliva increased exponentially across the 36 month follow-up period (from 3.43 to 1,281.69 copies/50 ng) and subsequently declined to undetectable levels post-tonsillectomy (Figure 1A).

Histologically Confirmed Diagnosis of an Occult P16INK4A Positive OPC

This individual was diagnosed as having a 2 mm squamous cell carcinoma (T1N0M0) in the left tonsil (Figure 1B) using Haemotoxylin and Eosin (H&E) staining. He had only foci of stromal invasion with a depth of <1 mm. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Further, HPV-16 DNA was only positive in left tonsillar tissue (Figure 1C). Immunohistochemistry (IHC) staining for p16INK4a demonstrated diffuse and strong staining in more than 70% of tumor cells (Figure 1D). However, the non-affected remainder of the left tonsil as well as the right tonsil were negative for p16INK4a with usual mosaic pattern of staining. The excision margins of the left tonsillar malignancy were widely clear. No atypia or malignancy could be identified in the right tonsil and bilateral tongue base specimens all of which were negative for HPV-16 DNA.

Discussion

Long-term persistence of HPV-16 infection is likely to be a prerequisite for the development of malignancy (13, 14). Women with persistent HPV-16 infection in the cervix for <1 year have a 40% risk of developing cervical intraepithelial neoplasia grade 2 or more within 3 years (13). Indeed, the natural history of HPV in the oropharynx from initial infection to carcinogenesis is not known with many questions remaining unanswered. Several studies have evaluated the prevalence of HPV-16 DNA in saliva (1518) without clinical assessment of positive individuals. Studies aimed at clinical assessment of those with persistence for premalignancy or microscopic carcinoma have failed to detect significant abnormalities (19). This has led to the assertion that screening for early occult or premalignant oropharyngeal lesions is not feasible. Here, we report the first ever histologically confirmed diagnosis of an asymptomatic occult OPC (T1N0M0) discovered by a theoretical screening test through the serial measurements of HPV-16 DNA in salivary oral rinse samples.

The impact of the pattern of salivary HPV persistence including changes in the absolute HPV viral DNA copies over time has never been investigated. The pattern of salivary HPV-DNA detection in this case demonstrates an exponential upward trend with the titer at first sample being 3.43 copies per 50 ng and the final titer before surgery of 1281.7 viral copies per 50 ng. This may represent progression of the lesion with subsequent shedding of increasing levels of HPV-16 DNA into the saliva. In future cases the presence of this pattern should be evaluated, as it may provide a critical marker for the progression of disease and hence a signal for intervention; indeed the pattern of viral copies in serial measurement may have more importance than the persistence itself.

This case also has important implications with regards to the natural history of the disease. The left tonsil was strongly positive for HPV 16 DNA outside the region of malignancy and as anticipated was p16INK4a positive only within carcinoma. This implies that the malignancy is likely to have developed in a wider field of HPV infection with only a component undergoing malignant change. The existence of a precursor lesion to OPC has long been doubted and is cited as one of the obstacles to OPC screening (16). This case demonstrates that very early lesions can be found in asymptomatic individual, and that they can potentially be eradicated with minimal morbidity.

The quest for a sensitive and specific screening test for HPV-driven OPC is of great importance. The uptake of HPV immunization in developed countries is variable and the developing world remains largely unimmunised. As sexual habits change in the developing world (20, 21) there is likely to be the same rapid expansion in this disease that we have witnessed in the United States and Europe and global burden will continue to rise. As the first singular case, this report does not act as direct evidence of the value of screening in a general population, however, it demonstrates a possible salivary screening test and pathway for the detection of microscopic OPC. It demonstrates that a screened individual can receive significantly less morbid treatment than would be required for the standard presentation at a more advanced stage. This report and previous studies (8, 11, 12, 22), support the value of a salivary oral rinse test as a potential screening tool. Unlike previously published work, our study is the first to demonstrate that continuous monitoring of HPV-16 DNA in salivary oral rinse samples can detect occult OPC.

Data Availability Statement

All datasets generated for this study are included in the article.

Ethics Statement

This study was approved by institutional ethics committees from the University of Queensland (UQ) [HREC No: 2014000679 and 2014000862]; Queensland University of Technology [HREC No: 1400000617 and 1400000641]; and the Royal Brisbane and Women’s Hospital (RBWH) [HREC/16/QRBW/447]. Written informed consent was obtained from this participant for publication of this case report.

Author Contributions

All authors have read and agree to the published version of the manuscript. KT and CP: conceptualization. All authors: methodology, validation, formal analysis, data curation, investigation, and writing—review and editing. KT, SV, and CP: writing—original draft preparation. CP: funding acquisition.

Funding

The prevalence study was funded by Janssen Biotech Inc.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Dr. Gert Scheper from Janssen Vaccines & Prevention B.V. We would also like to thank Lilian Menezes for her assistance in the recruitment of study patient and collection of clinical samples.

 

May, 2020|Oral Cancer News|