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Robotic surgery for oropharyngeal cancer not better than radiation therapy, study finds

Source: News Medical
Date: June 7, 2019
Author: Reviewed by James Ives, M.Psych (Editor)

In 2012, scientists at Lawson Health Research Institute launched the world’s first clinical trial comparing robotic surgery to radiation therapy for the treatment of oropharyngeal cancer (cancer at the back of the throat). The team is now reporting findings from the seven-year study which challenges beliefs that surgery leads to better swallowing outcomes, suggesting instead that radiation results in better quality of life for patients.

For Betty Ostrander, an operating room nurse from Tillsonburg, Ontario, a throat cancer diagnosis was life-changing. Betty was 59 when she discovered a small lump on the right side of her neck. After seeking medical care and testing, she was told she had oropharyngeal cancer.

“I remember thinking ‘I’m healthy, I eat right and I exercise; this can’t be happening to me.’ But it was, and it was scary,” recalls Betty. “One of the first questions I asked was whether there were any clinical trials available.”

Betty was one of 68 research participants in the ORATOR trial. The study included six centres from across Canada and Australia, including London Health Sciences Centre’s (LHSC) London Regional Cancer Program. Participants were randomized to receive either precision radiation therapy, often combined with chemotherapy, or transoral robotic surgery (TORS).

TORS is a surgical method for treating throat cancer which uses a small 3D camera and miniature robotic instruments to remove tumors. LHSC was the first center in Canada to offer TORS in 2011.

“Early studies suggested TORS might reduce the risk of swallowing problems historically associated with radiation and it therefore rose quickly in popularity,” explains Dr. Anthony Nichols, Associate Scientist at Lawson and Head and Neck Cancer Surgeon at LHSC. “But there was no randomized trial to compare patients’ swallowing outcomes. As the first center in Canada to offer TORS, we decided to tackle this problem through the ORATOR trial.”

The research team found no difference in survival between the two groups but, surprisingly, participants in the radiation group experienced better swallowing outcomes. A mild decline in swallowing function was observed in 40 per cent of the surgery participants compared to 26 per cent of radiation participants. All participants were able eat a full diet after treatment but 16 per cent from the surgery group said they needed to specially prepare their food.

Our findings challenge the notion that TORS leads to better swallowing outcomes. While radiation was previously associated with poor swallowing outcomes, treatments have advanced considerably and are now much more precise, which may be leading to better patient outcomes.”

Dr. David Palma, Associate Scientist at Lawson and Radiation Oncologist at LHSC

Patients in the surgery group were also at risk for dangerous bleeding during surgery. One year after treatment, patients in the surgery group were more likely to experience pain (22 per cent versus eight per cent in the radiation group), use painkillers (45 per cent versus 15 per cent), have issues with their teeth (12 per cent versus one per cent), and experience shoulder impairment.

The team found that patients in the radiation group experienced more short-term constipation and a temporary drop in blood counts. They also experienced an increased risk of tinnitus (ringing in the ears) and high frequency hearing loss when receiving chemotherapy, with some needing hearing aids.

“Each therapy has its different potential side effects but our findings suggest that TORS is not superior to modern radiation,” says Dr. Nichols. “We hope this research can be used by patients and their oncologists to help inform treatment decisions.”

Cases of oropharyngeal cancer have more than doubled since the 1990s. While throat cancer was more common in elderly patients with a history of heavy smoking or drinking, physicians have seen a dramatic rise in cases caused by human papilloma virus (HPV).

There is fortunately a high survival rate in patients with HPV-related throat cancer, leading researchers to study quality of life after treatment.

Drs. Nichols and Palma recently launched the ORATOR 2 trial which will further compare TORS against radiation and chemotherapy. The goal is to reduce the intensity of radiation and chemotherapy to improve quality of life while maintaining survival rates. The team aims to recruit 140 participants.

Results from the ORATOR trial were shared by Dr. Nichols at the American Society of Clinical Oncology’s Annual Meeting on May 31, 2019. The study was funded by the Canadian Cancer Society.

June, 2019|Oral Cancer News|

Queensland scientist develops new HPV cancer vaccine

Source: 9News
Date: May 22, 2019
Author: 9News Staff

*click Source to view video*

Former Australian of the Year Professor Ian Frazer has developed a vaccine aimed at treating HPV-related cancers of the head, neck, throat and tongue.

While funding is still being finalised, a trial of the vaccine is being prepared for people with incurable oropharyngeal cancers.

Professor Frazer, the Scottish-born immunologist who developed and patented the vaccine against HPV-related cervical cancer, has been working on this vaccine for nearly 15 years.

While the cervical cancer vaccine works as a preventative, this new vaccine is a treatment therapy.

It works by teaching the patient’s immune system to target the cancer cells containing HPV. The patient will then be given immunotherapy drugs that supercharge the immune system.

“This is all about a new way to treat cancer using the body’s defence against infection,” Professor Frazer said.

“This might give a second chance at life.”

HPV-related throat cancer kills three Australians every day.

“It’s going to become a major problem in Australia, in fact in the US we’ve seen an increase in HPV-related throat cancers by 225 per cent,” head and neck radiation oncologist Sandro Porceddu said.

Professor Porceddu will conduct the trial at the Princess Alexandra Hospital. It should begin towards the end of this year if a further $700,000 in necessary funding is found.

© Nine Digital Pty Ltd 2019
May, 2019|Oral Cancer News|

Greens and Genes

Source: Harvard Medical School
Date: May 16, 2019
Author: Jacqueline Mitchell

Your mother was right: Broccoli is good for you.

Long associated with decreased risk of cancer, broccoli and other cruciferous vegetables—the family of plants that also includes cauliflower, cabbage, collard greens, Brussels sprouts and kale—have now been found to contain a molecule that inactivates a gene known to play a role in a variety of common human cancers.

In a new paper published May 16 in Science, researchers led by Pier Paolo Pandolfi, the HMS Victor J. Aresty Professor of Medicine at Beth Israel Deaconess Medical Center, demonstrate that targeting the gene, known as WWP1, with the ingredient found in broccoli suppressed tumor growth in cancer-prone lab animals.

“We found a new important player that drives a pathway critical to the development of cancer, an enzyme that can be inhibited with a natural compound found in broccoli and other cruciferous vegetables,” said Pandolfi, who is also director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess.

“This pathway emerges not only as a regulator for tumor growth control, but also as an Achilles’ heel we can target with therapeutic options,” Pandolfi said.

One of the most frequently mutated, deleted, downregulated or silenced tumor suppressor genes in human cancersis PTEN. Certain inherited PTEN mutations can cause syndromes characterized by cancer susceptibility and developmental defects.

Because complete loss of the gene triggers an irreversible and potent failsafe mechanism that halts proliferation of cancer cells, it’s rare for both copies of the gene (humans have one copy from each parent) to be affected. Instead, tumor cells exhibit lower levels of PTEN. This raises the question of whether restoring PTEN activity to normal levels in the cancer setting can unleash the gene’s tumor-suppressive activity.

To find out, Pandolfi and colleagues identified the molecules and compounds regulating PTEN function and activation.

Carrying out a series of experiments in cancer-prone mice and human cells, the team revealed that a gene called WWP1, which is also known to play a role in the development of cancer, produces an enzyme that inhibits PTEN’s tumor-suppressive activity.

How to disable this PTEN kryptonite?

By analyzing the enzyme’s physical shape, the research team’s chemists recognized that a small molecule—formally named indole-3-carbinol (I3C), an ingredient in broccoli and its relatives—could be the key to quelling the cancer-causing effects of WWP1.

When Pandolfi and colleagues tested this idea by administering I3C to cancer-prone lab animals, they found that it inactivated WWP1, releasing the brakes on PTEN’s tumor-suppressive power.

But don’t head to the farmer’s market just yet. First author Yu-Ru Lee, HMS research fellow in medicine and a member of the Pandolfi lab, notes you’d have to eat nearly six pounds of Brussels sprouts a day, and uncooked ones at that, to reap their potential anti-cancer benefit.

That’s why the Pandolfi team is seeking other ways to leverage this new knowledge. The team plans to further study the function of WWP1 with the ultimate goal of developing more potent, and practical, WWP1 inhibitors.

Genetic or pharmacological inactivation of WWP1 with either CRISPR technology or I3C could “restore PTEN function and further unleash its tumor suppressive activity,” said Pandolfi. “These findings pave the way toward a long-sought tumor suppressor reactivation approach to cancer treatment.”

This work was mainly supported by the National Institutes of Health (grants R01CA82328 and R35CA197529).

In addition to Pandolfi and Lee, authors include Ming Chen, Jonathan D. Lee, Jinfang Zhang, Tomoki Ishikawa, Jesse M. Katon, Yang Zhang, Yulia V. Shulga, Assaf C. Bester, Jacqueline Fung, Emanuele Monteleone, Lixin Wan, John G. Clohessy, and Wenyi Wei, all of Beth Israel Deaconess; Shu-Yu Lin, Shang-Yin Chiang and Ruey-Hwa Chen of the Institute of Biological Chemistry; Tian-Min Fu and Chen Shen of Harvard Medical School; Chih-Hung Hsu, Hao Chen and Hao Wu of Boston Children’s Hospital; Antonella Papa of Monash University; Julie Teruya-Feldstein of Icahn School of Medicine at Mount Sinai; Suresh Jain of Intonation Research Laboratories; and Lydia Matesic of the University of South Carolina.

Disclosures: Pandolfi, Wei and Jain are cofounders of Rekindle Pharmaceuticals, which is developing novel therapies for cancer. All other authors declare no competing interests.

May, 2019|Oral Cancer News|

The Problem With Supplements

Source: Elemental
Date: May 6, 2019
Author: Markham Heid

Earlier this year, federal authorities announced plans to strengthen oversight of the supplement industry.

“The growth in the number of adulterated and misbranded products — including those spiked with drug ingredients not declared on their labels, misleading claims, and other risks — creates new potential dangers,” said U.S. Food and Drug Administration (FDA) commissioner Dr. Scott Gottlieb in a February press release.

Heightened oversight is needed, Gottlieb argued, because expansion and change within the supplement industry has made it difficult for his agency to keep pace. “What was once a $4 billion industry comprised of about 4,000 unique products, is now an industry worth more than $40 billion, with more than 50,000 — and possibly as many as 80,000 or even more — different products available to consumers,” he said.

From multivitamins and botanicals to probiotics and protein powders, roughly three out of four Americans now take some kind of supplement on a regular basis. Since the days of palliative tonics and snake-oil salesmen, Americans have been readily lured by the promise of health or longevity in the form of a drink, pill, or powder. While the terminology has evolved — “biohacking” and “nutraceuticals” are some of the buzzwords du jour — the implied benefits of most supplements still outpace or ignore the science. And despite recent studies that find supplements are frequently contaminated or that the best way to get nutrients is through food, Americans’ interest in supplements is only growing. And experts say many supplement users don’t recognize or appreciate the risks that accompany the use of these products.

“Pill use among every age group is at an all-time high,” says Dr. Mark Moyad, the Jenkins/Pomkempner director of preventive and alternative medicine at the University of Michigan. “There isn’t a medical condition or symptom you can name that doesn’t have a supplement you can take to treat or prevent it.”

“There’s a huge disconnect between people’s perception of supplements and the reality, and that can be really destructive.”

In some respects, the growth of the supplement industry is a good thing. As America’s population has grown older, fatter, and sicker, Moyad says there’s potential for targeted supplement use to fill in some nutrient shortfalls caused by unhealthy eating habits or disease-related deficiencies. There’s also little doubt that some groups — notably pregnant women and older adults — can benefit from taking certain supplements, he says.

“But the idea that you can take 10 pills a day and fix everything or live forever is faulty,” he says. “There’s a huge disconnect between people’s perception of supplements and the reality, and that can be really destructive.”

“Most supplements on the market are not tested for either efficacy or safety,” says Dr. JoAnn Manson, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital in Boston. She mentions heavy metal contamination and other concerns related to poor manufacturing practices, and compares the current regulatory environment to “the Wild West.” Just last year, a JAMA report found unapproved pharmaceutical ingredients have turned up in hundreds of products.

If you’re taking a handful of supplements without a doctor’s oversight, she says, “there’s the potential for almost anything to happen.”

In the mid-1980s, researchers at Seattle’s Fred Hutchinson Cancer Research Center, and elsewhere, were optimistic about the disease-fighting potential of antioxidants and vitamins.

Two in particular — beta-carotene and vitamin A — had shown promise in early dietary studies. “Beta-carotene is an antioxidant and a natural component of green and orange-yellow vegetables,” says Dr. Gilbert Omenn, who back then was at Fred Hutchinson and is now a professor of human genetics and molecular medicine at the University of Michigan. “Vitamin A was shown to reduce cell division and the proliferation of cancer cells.”

After gaining study approval from the National Cancer Institute, Omenn and his colleagues recruited more than 18,000 men and women who were at high risk for lung cancer. They randomly divided these volunteers into two groups; one took a placebo while the other swallowed a daily supplement containing 30 mg of beta-carotene and 25,000 IU of vitamin A.

Omenn says the goal of his government-funded study, which was known as CARET, was to lower cancer incidence. “We had beta-carotene for its antioxidant properties and vitamin A for its antiproliferative effect, and we thought it would be a nice combination,” he says.

The results of CARET were so disastrous that the trial had to be terminated almost two years early. Rather than lowering rates of lung cancer, the supplement had the opposite effect. Among the people taking it, “we saw one additional cancer case per thousand people,” Omenn says. That may not sound like a lot, but in the world of cancer statistics, an increase of one case per 100,000 people is significant.

“What we observed was maybe the most potent carcinogenic effect ever discovered,” he says. “It was truly shocking.”

What went wrong? It turns out that, when confronted with an overabundance of certain antioxidants, the human body may convert them into prooxidants, which have the potential to activate cancer pathways. “Something fundamental we didn’t understand in advance was that, in living systems, antioxidants are not antioxidants in all situations,” Omenn says.

Troublingly, another group of researchers more or less replicated Omenn and his team’s work in a later trial that looked at the effect of vitamin E and selenium supplements on prostate cancer incidence. Again, people at high risk for cancer were randomly assigned either a placebo or a daily supplement. And again, the study had to be ended early because cancer rates soared.

The lesson here isn’t that supplements give people cancer. Rather, it’s that approaching supplements as though they’re all upside is a misguided and potentially harmful operating philosophy. When you swallow a capsule packed with concentrated amounts of a vitamin, nutrient, or other substance — a practice that did not become widespread until very recently — you can get into trouble. “To this day, there remain people who believe vitamins and organic compounds are inherently safe and that our studies were flawed,” Omenn says. “But clearly, that’s not true.”

Omenn says that heavy doses of vitamin A can also promote bone pain or swelling, headaches, and skin problems among adults. Taken during pregnancy, large doses of vitamin A can cause birth defects, he says.

While individual supplements are unlikely to pack dangerous levels of vitamin A, people who take multiple supplements with overlapping ingredients may be playing with fire. “I see patients who come in with a whole bag of supplements they’re taking — an immune booster, something for hair, something for vision, something for skin — but if you look at the ingredients, you see they’re all the same,” says Dr. Zhaoping Li, a professor of medicine and director of clinical nutrition at UCLA Medical Center. “So someone is taking three or four things with vitamin A, and also a multivitamin with vitamin A, and all these can add up.”

Li explains that fat-soluble vitamins can accumulate in the body and cause liver toxicity. She says that, on rare occasions, she’s seen patients who needed liver transplants due to supplement overuse. But a more typical reaction to this sort of nutrient overdose could be elevated levels of inflammation accompanied by GI side effects like nausea and bloating, she says. “But these are nonspecific symptoms,” she adds, meaning doctors who see people with these issues probably wouldn’t associate them with supplement overuse.

While specifics vary from one product to the next, nearly all supplements come with some level of risk — including some of the most popular pills on the market today.

“When you talk about fish oil and omega-3, it’s very difficult and expensive to preserve the goodness of the fatty acids and to put it in capsules,” says Chandan Sen, associate vice president of research at the Indiana University School of Medicine. If fish oil is not properly preserved, he says, it becomes oxidized and potentially harmful. Taking such a product has “a similar impact on the body as taking over-fried cooking oil,” he explains.

Sen has written extensively on the risk and role of supplements. He says heavy-metal contamination is a common and well-documented issue associated with herbal products. He, and others, also point out that, time and again, research has shown that taking concentrated doses of food-derived or plant-derived nutrients does not confer the same benefits as eating the foods or plants themselves.

“In the cancer world, we tell people to avoid processed foods, and supplements by definition are processed foods.”

“It’s often harder for the body to metabolize an isolated vitamin or nutrient on its own,” says Lorenzo Cohen, a distinguished professor and director of the Integrative Medicine Program at the University of Texas MD Anderson Cancer Center in Houston. Cohen says that whole, unprocessed foods contain “a whole pharmacology” of different compounds and chemicals that together have a synergistic effect not found when those same chemicals are isolated and taken as supplements. It’s this synergy, he says, that seems to provide the greatest health benefit and the least amount of risk.

“Take curcumin, which is popular in the cancer world,” he says. Curcumin is found in turmeric root, and some research has found that it has antioxidant and anti-inflammatory properties. “When you consume curcumin as ground up turmeric powder and use it in cooking, you’re getting it with this rich soup of different phytochemicals and other constituents that are probably helpful,” he explains. On the other hand, taking concentrated curcumin in a capsule — even if its paired with other ingredients to boost its bioavailability — doesn’t seem to have the same effect, and it may come with risks, he says.

“In the cancer world, we tell people to avoid processed foods, and supplements by definition are processed foods,” he adds.

Sen echoes many of these warnings. “There’s evidence that berry anthocyanins may have potent anticancer chemopreventive effects,” he says. “But these anthocyanins have a very specific chemical structure.” When supplement makers try to extract these structures and put them into pills or powder, they often end up with a very different structure, he explains.

Sen says he’s interacted with many supplement companies. And his experience, by and large, has been that most of them spend far, far more of their budget on product marketing than on proper research and development. “This is clearly not in the best interest of consumers,” he says.

A common scenario, he explains, is that a small study performed in a “limited” experimental environment — for example, in cell cultures or in animals — will link a certain plant chemical with a potential health benefit. The media reports on this finding, and then a supplement maker rushes to manufacture a supplement using the relevant chemical, which they’ll claim is “science-backed.”

“The current legal landscape permits this,” he says. “To regulate everything is not the answer, but the barrier of entry into the marketplace for supplements is very low.”

In his February press release, FDA’s Gottlieb detailed plans to beef up his agency’s research efforts and product-reporting requirements. The FDA has since announced plans to heighten public awareness of adulterated products. But experts say these changes, while welcome, won’t address many of their core concerns.

“There are really no laws that make supplement companies go through the FDA in the first place,” says Joanna Sax, a professor of law at California Western School of Law who has published papers on the supplement industry.

Sax explains that, unlike prescription drugs or over-the-counter medications, nutrition and health supplements are legally categorized as food products. This makes them exempt from many forms of oversight. “Drugs have to be tested for safety and efficacy before they go to market,” she says. “But in most cases, the FDA can remove a supplement from the market only if there’s a demonstrated harm, and they don’t know if there’s a harm until that harm has already happened.”

The FDA’s authority comes from Congress, she adds, and so their power to prevent risky supplements from getting into consumers’ hands is limited. (The FDA declined to comment for this story.)

There’s a counterargument to be made that, were the FDA granted the power to demand pharmaceutical-level testing of supplements, many people would be denied affordable access to products that could provide them real and meaningful benefits.

“Pharmaceuticals need to be vetted for efficacy and safety, and approved by the FDA through a process that can take 10-plus years and many, many millions of dollars,” says Amy Brown, an associate professor in complementary and integrative medicine at the University of Hawaii at Manoa who has researched herb and dietary supplements. “This process is not possible for dietary supplements that are not patented,” she says. The costs would chase away most manufacturers.

Still, other experts say change is needed. “I absolutely do think there should be increased regulatory oversight and supplement makers should have to show that their products are safe,” says Brigham and Women’s Manson. “Many come with risks and very few benefits.”

Regardless of how supplements are regulated, experts say it’s time people started thinking of these products as akin to prescription drugs.

“There’s a lot of distrust of the drug industry, and I think some consumers trust supplements more because they see them as ‘natural’ and not made by the drug companies,” Sax says. The irony is that the recent growth in the consumer supplement industry has largely been fueled by drug companies entering the fold.

“It used to be supplements versus Big Pharma, but now they’ve merged — supplements are Big Pharma,” UM’s Moyad says. “The drug companies saw how big complementary health was getting and they wanted a piece of the action.”

“There is a desire to go from point A to point B as quickly and easily as possible, and taking pills to do that is very chic right now.”

Based on his 33 years in medicine — much of which he’s spent studying supplements — Moyad says he approaches these products with the same caution he applies to drugs. “I understand and respect the power of pills,” he says. Like prescription drugs, supplements can help people with a diagnosed medical condition or deficiency. And like pharmaceuticals, supplements come with risks and side effects, he says.

He also practices what he preaches. “My colleagues can’t believe I don’t take anything,” he says. “And I tell them I don’t take anything, first of all, because I don’t need to take anything, and also because I’m not willing to be a guinea pig in a clinical trial of one.”

Asked for examples of times when supplements are clearly beneficial, he says there’s strong evidence that some products can benefit those at high risk for macular degeneration or skin cancer. There’s also good evidence that supplements can treat some disease-related symptoms.

There’s also no question that certain patient groups — as well as adults who, by choice or by necessity, are deficient in certain vitamins or nutrients — can make up shortfalls with supplements. “I’m primarily vegan, so I take a vitamin B12 supplement,” MD Anderson’s Cohen says. But he adds that, for healthy adults looking to mitigate their disease risks, supplements offer more downside than upside. “In the best case, they’re just a waste of money and you pee them out,” he says. “The worst case is over time there’s some kind of accumulation and toxicity.”

Over and over again, he and other experts say that eating a range of healthy whole foods is a better, safer, more-effective approach than taking supplements.

“Eat at least five servings a day of fruits and vegetables, eat whole grains rather than refined grains, avoid processed foods, eat at least two servings of fish a week,” Manson says. “If you’re vegetarian, try to get fatty acids from oils and nuts and seeds.”

Moyad agrees. “I have yet to come across any product that someone could sell me that was the secret to health or longevity,” he says. “But all the boring shit — a healthy diet, a good night’s sleep, exercise — the evidence for that has only become stronger.”

“There is a desire to go from point A to point B as quickly and easily as possible, and taking pills to do that is very chic right now,” he says. “I think we’ll get to a place where some supplements could have incredible value in disease treatment, but people need to wake up to the fact that if they’re experimenting on themselves with these products today, they could wake up in a few years and have done real harm.”

May, 2019|Oral Cancer News|

Tackling side effects in head and neck cancer treatment – the end of the road for hyperbaric oxygen?

Source: Cancer Research UK
Date: May 2, 2019
Author: Katie Roberts

Some side effects appear years after cancer treatment. That’s the case for one side effect of radiotherapy for head and neck cancer, called osteoradionecrosis.

This painful condition results from damage to the jaw bone, which often doesn’t heal properly and can cause bone fractures or even bone death.

It can develop without an obvious trigger, but it’s often linked to dental work like tooth extractions or implants. And it can happen even if the dental work is carried out 20 years after radiotherapy.

Professor Richard Shaw, a Cancer Research UK-funded head and neck surgeon at the University of Liverpool, treats the difficult condition quite frequently through reconstructive surgery.

Shaw says that these procedures are often bigger and harder than patients’ original cancer surgery, because they’ve already had so much treatment in that area.

For that reason, researchers have looked for ways to prevent osteoradionecrosis from developing. And that’s where hyperbaric oxygen comes in. It started with a small trial in the 80s, which has influenced the way doctors prepare patients for dental surgery ever since.

But new Stand Up To Cancer trial data, led by Shaw and published in the International Journal of Radiation Oncology, shows the hyperbaric oxygen hype may have been a bit premature.

The trial of hyperbaric oxygen

Back in the 1980s, a small trial in the US showed that giving hyperbaric oxygen before dental surgery could reduce the risk of osteoradionecrosis developing.

What is hyperbaric oxygen therapy?

Hyperbaric oxygen treatment involves sitting in a chamber where the oxygen is at a higher pressure than the air we normally breathe. It’s thought the increase in oxygen can help to promote healing. Sessions typically last 60-90 minutes.

“Prevention is obviously a very good idea, but I think there was concern around whether hyperbaric oxygen was the answer,” says Shaw.

A big question that lingered around the treatment was how applicable the 34-year-old trial results were to patient’s today. Radiotherapy has become a lot more targeted than it was a few decades ago, which may affect the risk of someone developing osteoradionecrosis.

“There really was no recent, good evidence for hyperbaric oxygen,” says Shaw.

No one wants to take the risk with our patients who, after all, had been cured of head and neck cancer and saw themselves as long-term survivors.

– Professor Richard Shaw

The verdict’s in

Shaw and his team ran a trial testing hyperbaric oxygen treatment in 144 patients who’d had head and neck cancer and now needed dental surgery. Half the patients had a course of hyperbaric oxygen before surgery, the other half didn’t.
Patients were then monitored after dental treatment to see who developed osteoradionecrosis, as well as monitoring pain levels and quality of life.

The first thing the team learnt was that osteoradionecrosis is a lot less common now than it was in the 80s.

“We can now say that with modern radiotherapy, someone’s risk of having this jaw problem is about 1 in 20. Which is a lot lower than the previous trial, which had shown it was around 1 in 3,” says Shaw.

The other big finding was that hyperbaric oxygen had no impact on the number of people developing osteoradionecrosis – the numbers were pretty much the same in each side of the trial.

And although people who had hyperbaric oxygen reported fewer short-term side effects and less pain immediately after surgery, there was no difference in long-term pain or quality of life between the two groups.

“It’s very clear that in our health system, hyperbaric oxygen is no longer justified,” says Shaw. “In some ways it could be reported as a negative finding, because hyperbaric oxygen didn’t work. But I think it has given us a definitive change of practice.”

What’s next?

As well as changing practice, the trial leaves another legacy: patient samples. Shaw is planning to use these to understand more about who develops osteoradionecrosis.

“What you’ll deduce with 6% of patients developing osteoradionecrosis in this trial is that 94% of people didn’t, even though they were considered high risk,” he says.

Right now, risk is assessed based on where the radiotherapy was aimed, as well as the type of follow-up dental work that’s being done. But Shaw believes risk could be predicted more precisely. The team will now study the patient samples to look if there are any differences in the DNA of patients who went on to develop osteoradionecrosis.

“We’re looking for a genetic signal or a ‘fingerprint’ that identifies people at high risk of osteoradionecrosis that we could validate in future trials,” says Shaw.

For now, Shaw says doctors can help to reduce the risk of osteoradionecrosis by making sure patients’ teeth are in the best possible condition before and after radiotherapy.

This, Shaw says, could help make sure “these conditions that require surgery don’t arise in the first place.”

May, 2019|Oral Cancer News|

Oral HPV DNA Persistence After Head and Neck Cancer Treatment Linked to Disease Progression

Source: genomeweb
Date: May 2, 2019
Author: Staff Reporter

NEW YORK (GenomeWeb) – Persistent traces of human papilloma virus DNA after treatment for HPV-positive head and neck cancer is linked to an increased recurrence risk, a new study has found.

Head and neck cancers affect some 53,000 people in the US each year, according to the National Cancer Institute, and HPV has been implicated in many of those cases. In general, patients with HPV-positive tumors have higher survival rates than those with HPV-negative tumors.

A team of MD Anderson Cancer Center-led researchers collected oral rinse samples from nearly 400 patients with head and neck squamous cell carcinomas at diagnosis and as their treatments progressed. As they reported today in JAMA Oncology, the researchers found that viral load in patients’ oral samples broadly decreased as they underwent therapy. But some patients’ viral loads persisted despite treatment, which was linked to an increased risk of cancer recurrence and death, the researchers reported.

“Our data suggest that a subset of patients with HPV-positive HNSCC at high risk for locoregional recurrence can be identified by detection of persistent, oral HPV after treatment,” MD Anderson’s Maura Gillison and her colleagues write in their paper.

The researchers enrolled 396 patients with oral cavity, oropharyngeal, or unknown primary HNSCC in their study. They tested the patients’ tumors for the presence of 13 high-risk HPV types using an mRNA expression test and found 202 patients had HPV-positive tumors.

At the same time, the researchers collected oral rinse samples from patients at diagnosis, after surgery, and at six months. Additionally, patients who underwent radiotherapy provided weekly oral rinse samples. The researchers tested these samples — a total of 2,922 oral rinse samples — for the presence of HPV using a multiplex PCR-based approach.

At diagnosis, patients with HPV-positive tumors were significantly more likely to have oral rinse samples positive for HPV than were patients with HPV-negative tumors. In particular, the researchers reported that the detection of any oral HPV DNA had a sensitivity of 84 percent, a specificity of 88 percent, a positive predictive value of 88 percent, and a negative predictive value of 84 percent for the diagnosis of an HPV-positive tumor.

The prevalence of oral HPV DNA, though, went down after treatment, the researchers reported. Prior to treatment, the prevalence of HPV DNA in oral rinses that matched that of HPV in the tumor sample was 69 percent. But after primary surgical resection, it was about 14 percent. Its prevalence fell similarly for patients who underwent radiotherapy, going from 85 percent before treatment to 9 percent after radiotherapy.

As expected, overall and recurrence-free survival was higher for patients with HPV-positive tumors than with HPV-negative tumors. Patients with HPV-positive tumors had a two-year overall survival of 91 percent, as compared to 75 percent for patients with HPV-negative tumors.

But for a subset of patients with HPV-positive tumors — about 14 percent — the prevalence of oral HPV DNA didn’t decline with treatment. These patients were more likely to recurrent disease, with about 45 percent experiencing disease recurrence within two years. Additionally, this subset had a lower two-year overall survival of 68 percent.

These patients, the researchers noted, might benefit from increased surveillance or adjuvant therapy.

The researchers added that their findings suggest that oral rinses to detect HPV DNA in head and neck cancer patients might be helpful. They cautioned, though, that its clinical utility might be limited by the need to identify tumor-type infections.

“Ongoing studies will evaluate whether multiplexed detection of plasma HPV DNA can improve these limitations,” the researchers added.

NOTE: This research was paid for in part by the Oral Cancer Foundation,www.oralcancer.org

May, 2019|Oral Cancer News|

E-cig users develop some of the same cancer-related molecular changes as cigarette smokers

Source: EurekAlert!
Date: February 14, 2019

If you think vaping is benign, think again.

A small USC study shows that e-cig users develop some of the same cancer-related molecular changes in oral tissue as cigarette smokers, adding to the growing concern that e-cigs aren’t a harmless alternative to smoking.

The research, published this week in the International Journal of Molecular Sciences, comes amid a mushrooming e-cig market and mounting public health worries. On a positive note, recent research found vaping is almost twice as effective as other nicotine replacement therapies in helping smokers quit.

But among adolescents, vaping now surpasses smoking, and there’s evidence that e-cig use leads to nicotine addiction and future smoking in teens.

“The existing data show that e-cig vapor is not merely ‘water vapor’ as some people believe,” said Ahmad Besaratinia, an associate professor at Keck School of Medicine of USC and the study’s senior author. “Although the concentrations of most carcinogenic compounds in e-cig products are much lower than those in cigarette smoke, there is no safe level of exposure to carcinogens.”

Besaratinia emphasized that the molecular changes seen in the study aren’t cancer, or even pre-cancer, but rather an early warning of a process that could potentially lead to cancer if unchecked.

The researchers looked at gene expression in oral cells collected from 42 e-cig users, 24 cigarette smokers and 27 people who didn’t smoke or vape. Gene expression is the process by which instructions in our DNA are converted into a functional product, such as a protein. Certain alterations in gene expression can lead to cancer.

They focused on oral epithelial cells, which line the mouth, because over 90 percent of smoking-related cancers originate in epithelial tissue, and oral cancer is associated with tobacco use.

Both smokers and vapers showed abnormal expression, or deregulation, in a large number of genes linked to cancer development. Twenty-six percent of the deregulated genes in e-cig users were identical to those found in smokers. Some deregulated genes found in e-cig users, but not in smokers, are nevertheless implicated in lung cancer, esophageal cancer, bladder cancer, ovarian cancer and leukemia.

Besaratinia and his team plan to replicate his findings in a larger group of subjects and explore the mechanisms that cause gene deregulation. He’s also launching another experiment in which smokers switch to e-cigs; he wants to see whether any changes in gene regulation occur after the switch.

“For the most part, the participants are as curious as we are to know whether these products are safe,” he said.

In addition to Besaratinia, the study’s other authors are first author Stella Tommasi, Andrew Caliri, Amanda Caceres, Debra Moreno, Meng Li, Yibu Chen and Kimberly Siegmund, all of USC.

The research was supported by grants from the National Institute of Dental and Craniofacial Research of the National Institutes of Health (1R01DE026043) and the University of California Tobacco-Related Disease Research Program (TRDRP-25IP-0001 and TRDRP-26IR-0015).

February, 2019|Oral Cancer News|

Merck’s Keytruda looks to zoom past Opdivo with fast head and neck cancer review

Source: Fierce Pharma
Date: February 11, 2019
Author: Carly Helfand

Merck & Co.’s Keytruda is duking it out with Bristol-Myers Squibb’s Opdivo in the head and neck cancer marketplace, but Keytruda just took one step toward a green light that would give it a big edge.

The FDA has tagged Merck’s approval application for the immuno-oncology superstar—alone or in tandem with chemo—with its priority review designation in previously untreated patients with head and neck cancer. The move, which Merck announced Monday, sets Keytruda up for a quick trip down the regulatory pathway; the agency expects to have a decision by June 10, Merck said.

FDA staffers based their decision on data Merck trotted out at last year’s European Society for Medical Oncology (ESMO) meeting in October. Results showed that solo Keytruda, when pitted against a standard-of-care regimen dubbed by doctors as “Extreme,” could cut the risk of death by 22% in patients testing positive for the biomarker PD-L1. In patients with high levels of PD-L1 in their tumors, that figure shot up to 39%.

And when paired with chemo, Keytruda pared down the risk of death by 23% regardless of patients’ PD-L1 status.

Based on “the limited interaction we’ve had with key opinion leaders, I think this is seen as practice-changing,” Roy Baynes, Merck SVP and head of global clinical development, said when the data were released. And in addition to shaping opinions on clinical practice, the results also confirmed Keytruda’s place in the second-line setting, where it had previously suffered a narrow trial miss.

If Merck can snag a go-ahead in new patients, it’ll be an option for the more than 65,000 patients diagnosed each year in the U.S., according to the company. It’ll also mean a major leg up on BMS, whose Opdivo only bears a second-line OK. And with untreated patients in line to get Keytruda, the number of patients eligible for Opdivo—because those who used Keytruda first wouldn’t be in line for a second round of PD-1 therapy—will presumably dwindle.

The two drugs have been battling it out in different tumor types since the early days of immuno-oncology, when both started off with FDA nods in melanoma. While Opdivo has held market leads in important areas including kidney cancer, it’s Keytruda that has the No. 1 position, thanks to its dominant status in lung cancer, the biggest arena for the medicines.

February, 2019|Oral Cancer News|

Tumor Mutational Burden Predicts Who Will Respond to Immunotherapy

The advent of immunotherapy has significantly shifted the treatment paradigm and prognosis for multiple advanced-stage cancers. In cancers like metastatic melanoma and non–small cell lung cancer (NSCLC), the treatment class has greatly improved survival rates.

However, not all patients respond to the treatments, highlighting the need for predictive biomarkers to determine which patients will benefit. Early reports and small cohorts have suggested high tumor mutational burden being associated with improved clinical response, and now a large study has confirmed the hypothesis.

“Given the potential toxicities of immunotherapy and the highly variable response to immune checkpoint inhibitors, as well as the significant economic cost of these agents, there is an urgent need for biomarkers that can predict immunotherapy response,” explained the researchers of the study.

Looking at data from more than 1000 patients with stage IV or metastatic disease for which immune checkpoint inhibitors are approved, including NSCLC, melanoma, renal cell carcinoma, bladder cancer, and head and neck cancer, researchers found that higher somatic tumor mutational burden is associated with improved overall survival.

Patients were treated with atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, or tremelimumab. Tumor mutational burden was calculated by normalizing the number of somatic nonsynonymous mutations to the total number of megabases sequenced, and noting that mutational load varies across tumor types, the researchers defined tumor mutational burden within each cancer type.

The authors found that, across all cancers, more mutations translated into improved overall survival. The authors noted that the association remained even when removing NSCLC and melanoma from the analysis.

“Although the effect for some individual cancers did not reach statistical significance, possibly because of smaller sample size, the numerical trend of better overall survival was observed in nearly all cancer types, with glioma the clearest exception,” the authors wrote. These findings mirror real-world evidence, which has shown gliomas to be immunosuppressive and remain difficult to treat.

Of note, what constituted as high tumor mutational burden varied greatly by cancer type, which suggests that there is likely not a viable universal number that could define high tumor mutational burden and be predictive of response to immune checkpoint inhibitors across all cancers. While breast cancers and renal cell carcinomas only need 6 mutations per 1 million DNA to predictably respond well to immune checkpoint inhibitors, melanomas need 30.7 and colorectal cancers need 52.2.

According to the researchers, this can likely be explained by distinct tumor microenvironments as well as other factors that have shown to independently predict response, including clonality, immune infiltration, and immune cell exclusion.

Reference:

Samstein R, Lee C, Shoushtari A, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types [publihsed online January 14, 2019]. Nature. doi: 10.1038/s41588-018-0312-8.

January, 2019|Oral Cancer News|

Researchers Uncover Major Clue In Predicting Response To Immunotherapy

Researchers at Memorial Sloan Kettering Cancer Center in New York have discovered that cancer cells with high numbers of faults in their DNA are more likely to respond to immune checkpoint inhibitors (ICI), a major class of immunotherapy drugs, which includes Keytruda.

The study, published today in Nature Genetics adds important pieces to the puzzle as to why some cancer patients respond to immunotherapy whereas others do not. The researchers measured ‘tumor mutation burden (TMB)’, essentially counting how many DNA faults a tumor contains by looking for errors in the DNA sequence.

“People assume that TMB is important in predicting response to immunotherapy in all cancers, but up until now, all we’ve had is data from small studies and clinical trials on mostly lung cancers and melanoma,” said Luc Morris, MD, surgical oncologist at Memorial Sloan Kettering Cancer Center and one of the lead authors of the paper.

The researchers studied the DNA of 1,662 patients with advanced cancer (classified as stage IV or metastatic disease) treated with one or more of several FDA-approved ICI drugs and DNA from 5,371 patients with advanced cancer who had not had ICI. They used a tool called MSK-IMPACT, which looks at just 3% of the coding-regions in DNA, but is correlated to the number of mutations in the genome.

“Is TMB associated with likelihood that immunotherapy has benefit? Is this true in all cancers? We wanted to find out whether TMB had broad applicability,” said Morris.

The researchers found that if they took the 20% of cancers in their data with the most mutations, these people responded better to ICI than those with lower numbers of mutations in their tumors.

However, this correlation did not hold true for all tumors, for example, in people with a type of brain cancer called glioma, those with TMB in the top 20% did no better on ICI than those with lower TMB. Also in breast cancer there was no conclusive evidence that a higher TMB predicted response to ICI, although the study included relatively few breast cancer patients as ICI is not currently widely used for the disease.

Researchers don’t exactly know why high numbers of mutations make cancers more susceptible to immunotherapy, but they do have a very plausible theory. They think that the more mutated a cell is, the more likely it is to produce incorrect, mangled proteins. These displayed on the cell surface are called neoantigens and they are so far from what would be considered normal, the immune system identifies them as foreign and attacks the cells.

This is not a unique study in concept, with previous research on a smaller number of cancers of specific types, notably lung and melanoma, indicating that TMB is likely predictive of immunotherapy response. However, it is the largest and most comprehensive study to date, providing the most persuasive evidence that this is true for a greater number of cancer types.

“Only in lung cancer is TMB being used in a clinical trial. Hopefully this data will give us permission to include it in future clinical trials on other cancer types,” said Morris.

However, some patients with high TMB don’t respond to ICI at all, so there is still work to be done to figure out why high TMB is not a universal predictor of response to ICI.

“TMB by itself is not going to give you a high confidence in predicting whether a patient is going to respond to immunotherapy or not. It is one biomarker for response, but a number of other factors are important. I would not suggest you take the data from this paper and apply it to a patient in the clinic,” said Morris.

January, 2019|Oral Cancer News|