Human Papillomavirus and Oral Cancer - Looking Toward the Clinic

6/18/2008
web-based article
Caroline McNeil
JNCI Journal of the National Cancer Institute 2008 100(12):840-842 Head and neck cancer researchers are considering clinical studies, including a proposed cooperative group treatment trial, that would investigate the link between human papillomavirus (HPV) and some oral cancers. Although the studies are still in the planning stage, they mark a new turn toward the clinic for an area that up to now has centered mostly on epidemiologic and laboratory studies.

Over the past decade, population studies have established an association between HPV and some tumors in the oropharynx (tonsils, soft palate, posterior pharynx, and base of tongue). Much remains unknown about the biology and natural history of oral HPV infection, but evidence of its association with these tumors is so strong that the International Agency for Research on Cancer concluded, in a monograph published in December, that there is "sufficient evidence in humans for the carcinogenicity of HPV16 in the oral cavity and oropharynx."

Now researchers are beginning to ponder the clinical implications of this link. Especially intriguing to many are data suggesting that HPV-positive oropharyngeal tumors respond better to treatment than HPV-negative tumors. That finding has given rise to important clinical questions, including the one to be addressed in the proposed trial: Can HPV-positive tumors be treated less aggressively than HPV-negative tumors because of their increased sensitivity to chemotherapy and radiotherapy?

"That's the fundamental question," said Arlene Forastiere, M.D., a professor at the Johns Hopkins Kimmel Cancer Center in Baltimore and a leader in the Eastern Cooperative Oncology Group, which is discussing the possibility of such a trial. "Should they be treated the same or differently?"

The difference in response rates is not the only aspect that sets HPV-positive tumors apart from HPV-negative tumors. Studies suggest that the tumors have different molecular and histologic features, that HPV-positive patients survive longer, and that their risk factors and demographics are distinct. HPV-positive patients are more likely to be young and less likely to smoke cigarettes or use alcohol than HPV-negative oral cancer patients. A prospective study published last year in the New England Journal of Medicine showed that HPV-positive tumors were strongly associated with multiple oral sex partners. Most recently, a case–control study ( J Natl Cancer Inst 2008;100:407–20) showed that HPV-positive oropharyngeal tumors are not influenced by alcohol or tobacco use, setting them apart from HPV-negative tumors, which are strongly associated with drinking and smoking.

"The risk factors are completely distinct and do not overlap," said Maura Gillison, M.D., Ph.D., a Hopkins cancer researcher and lead author on this study as well as the New England Journal of Medicine article. "These are actually completely different cancers that happen to occur in the same place," she said.

Others demur. This is "very groundbreaking work," said Jatin Shah, M.D., chief of the head and neck service at Memorial Sloan-Kettering Cancer Center in New York, "but it remains to be proven that these are distinct pathological entities." Tissue samples from HPV-positive and HPV-negative tumors look alike, he argues. And although HPV-positive patients have a better chance of responding to chemoradiation, the reasons are unknown. "This is a very provocative question," he said. "We need more research in the lab to answer it."

The question is particularly urgent in oropharyngeal cancer because of the acute and prolonged toxicity of current treatments, Shah said. The treatment can result in lifelong problems with swallowing and speech. And for HPV-positive patients, who are more likely to be young, that can mean many decades of severely impaired quality of life.

Still Hypothetical

Nevertheless, Shah and others warn against modifying the standard treatment now. Forastiere, who chairs the head and neck committee of the National Comprehensive Cancer Network, said that "it would be premature to make practice changes ... quite dangerous, really." The cancer network's 2008 treatment guidelines for orophyryngeal cancer will not mention HPV status, she said. "The next steps are really in clinical trials."

The link between HPV and oropharyngeal cancer also raises the possibility of targeting those tumors with a therapeutic vaccine. At Hopkins, Gillison and her colleagues have completed a phase I trial with an experimental treatment vaccine and are now analyzing the data. After 2 years of follow-up, she said, all 18 patients in the trial were doing well.

And if further studies confirm that HPV-positive patients have better response rates and survival, their improved prognosis could affect the staging system for head and neck cancers. Though a long way off, that possibility is already the subject of conjecture. Gillison said that, someday, HPV-positive and HPV-negative tumors might be staged as two separate diseases, in the way that small-cell and non–small-cell lung cancer are.

Shah, who chairs the head and neck section of the American Joint Committee on Cancer, which develops, maintains, and revises the tumor–node–metastasis staging system used in most cancers, said that one possibility would be to consider HPV status as an additional factor that influences prognosis. This factor may be considered in the future, he said, and could be similar to the way additional factors affect stage in other cancers. In thyroid cancer, for instance, anyone younger than 45 years is downstaged to a stage 1 or 2, even with distant metastases.

But HPV's effect on oropharyngeal staging is still hypothetical, Shah emphasized. The joint committee is not considering any changes to the current system. "The time may come when HPV status will be a factor," he said, "but there needs to be a lot more science before that."

Prevention and Screening?

The link between HPV and oropharyngeal cancer also has potential implications for prevention. Will it ever be possible, for instance, to detect precancerous changes in the oropharynx, as in the cervix, with the help of HPV-based screening?

Detecting signs of oral HPV infection is not difficult—in oral rinses, for instance. But finding evidence that the viral DNA has been integrated into oropharyngeal basal cells and identifying submucosal, premalignant changes before they become visible is "a bit trickier," Gillison said.

An even more fundamental barrier to screening is a lack of knowledge on how, or even whether, persistent oral HPV infection progresses to premalignant changes in the oropharynx.

"We don't know what the infection looks like in premalignant cells. We don't know if premalignant lesions in the oropharynx relate to HPV," said Aimee Kreimer, Ph.D., in the division of cancer prevention at the National Cancer Institute in Bethesda, Md. "It's so new. We don't know the natural history of oral HPV infection."

Shah said that studies are needed to show whether oral HPV infection progresses to dysplasia, as it does in cervical cancer. Doing so would take a prospective, longitudinal study of people with HPV infection, followed by visual detection of premalignant changes, he said. Or researchers might look for surrogate markers of progression by using random biopsies. "I don't know if anyone is doing this, but it would be an exciting project," he said. "It's the logical next step."

One smaller step toward understanding the natural history of HPV oral infection is a study, now in a pilot stage, designed to look at the persistence of these infections, Kreimer said. The study will be nested in a larger study—led by Anna Giuliano, Ph.D., at the H. Lee Moffitt Cancer Center in Tampa—which is monitoring men to evaluate anal and penile HPV infections.

Primary prevention of oropharyngeal cancers is another possibility that intrigues HPV researchers. Current HPV vaccines, designed to prevent cervical cancer, could theoretically prevent HPV-positive oropharyngeal cancers as well. Both Merck's Gardasil and GlaxoSmithKline's Cervarix (which was approved in Australia but not yet in the U.S.) target HPV16, which is implicated in most HPV-positive oropharyngeal cancers. And animal studies suggest that vaccination will prevent oral cancers. Hopkins researchers have proposed a prevention study to Merck, but when contacted for this article, a company spokesperson said that it is not currently working on plans for such a trial.

However, other studies may provide some data on this issue. Kreimer said that the NCI is considering adding an oral HPV component to its follow-up study of women in Costa Rica who participated in a trial of GlaxoSmithKline's prevention vaccine. The study would compare the prevalence of oral HPV infection among women who received the vaccine with women who did not.

More studies—of all kinds—are likely. The NCI head and neck steering committee will convene a state-of-the-science meeting in November to help identify and prioritize research needs, said Claudio Dansky Ullmann, M.D., NCI's lead for head and neck cancer trials, who serves on the steering committee. "We will bring the top experts in this area to discuss the current status of things and, we hope, to lay a platform plan for the development of future translational and clinical studies to advance the field," he said.

And there seems little doubt that some of those studies, such as the proposed treatment trial, will explore whether HPV-positive and HPV-negative patients should be treated differently. "We find the data indicating that HPV-positive and HPV-negative cancers are distinct disease entities to be compelling," Forastiere wrote in an e-mail. "Consequently, we are factoring this into clinical research questions and trial designs going forward." (www.oralcancerfoundation.org)

Primary Tumors Can Drive the Growth of Distant Cancers

6/23/2008
web-based article
staff
Biocompare Life Science News (www.biocomare.com) Primary tumors can encourage the growth of stray cancer cells lurking elsewhere in the body that otherwise may not have amounted to much, according to a new study in the June 13 issue of the journal Cell, a publication of Cell Press. As people age, most may have such indolent cancer cells given the sheer number of cells in the body, although their rarity makes them impossible to detect, the researchers said.

The primary tumors under study, which were derived from human breast cancers, seem to "instigate" the growth of other cancers by mobilizing bone marrow cells, which then feed the secondary tumors' growth, they report.

One key to the process is the secretion of a substance known as osteopontin by the instigating tumor, a finding that may have therapeutic implications. Indeed, the researchers noted that osteopontin is present at elevated levels in women with metastatic breast cancer, supporting the notion that the new findings may hold clinical significance.

"If metastases depend on stimulation by primary tumors, interception of the signal through neutralizing antibodies" might block cancer spread, said Robert Weinberg of the Massachusetts Institute of Technology. "That's still speculative, but it's an interesting idea to ponder," he added, noting that treatments today don't specifically target metastases, which are responsible for the vast majority of cancer deaths.

The researchers noted that while the effects of the tumor microenvironment has been much studied, much less was known about how the systemic environment in the body contributes to tumor growth. Several earlier reports had shown that assorted bone marrow-derived cells can be incorporated to various extents into the supportive framework, or stroma, of tumors. However, it wasn't clear whether tumors actively recruit stromal cells by directly perturbing other cell reservoirs, such as the bone marrow, or whether tumors are just passive recipients of stromal cell precursors that normally circulate throughout the body.

In the new study, the researchers injected "instigating" human tumor cells into mice along with indolent "responding" cancer cells also derived from humans. Those indolent cells formed vigorously growing tumors only in the presence of the instigating tumor cells, they reported. They found further evidence that the instigating tumor somehow perturbs the makeup of the bone marrow, although Weinberg said they don't really know how that happens. They also show that osteopontin is necessary to the process, but that it does not act alone.

Finally, they showed that the same instigation process can encourage the growth of disseminated metastatic cancer cells. Instigating breast tumors in the mice also drove the growth of implanted fragments of human colon tumors, a finding that they said shows the generality of the physiologic signaling.

Nonetheless, the researchers said they don't yet know how universal this systemic instigation of tumor growth might be. Still, the findings challenge the "prevailing view that primary tumors suppress the growth of derived metastases," Weinberg said. "We argue they can foster cancer's spread by activating bone marrow that is then recruited by distant metastases."

The findings also have important implications for the preclinical study of human cancers, Weinberg emphasized.

"The ability of instigating tumors to foster the growth of a human colon tumor surgical specimen underscores the powers of systemic instigation," the researchers wrote. "Indeed, to our knowledge, methods to expedite the growth of human tumor surgical specimens in vivo have not been previously described. These results suggest that the presently described procedure can be used to study aspects of human tumor biology that would otherwise be difficult if not impossible to study.

"In the longer term, identification of additional tumor-derived factors that perturb the host systemic environment in one way or another may allow one to predict the effects that a given primary tumor type has on the outgrowth of indolent cancer cells that have disseminated to distant sites."

George Moore, 88; doctor linked mouth cancer to chewing tobacco

6/23/2008
Los Angeles, CA
Thomas H. Maugh II
Los Angeles Times (www.latimes.com) Dr. George E. Moore, the cancer researcher who was among the first to link chewing tobacco to mouth cancer and who built the Roswell Park Memorial Institute in Buffalo, N.Y., into a major cancer research center, died May 19 in Conifer, Colo. He was 88. The cause of death was bladder cancer, according to his family.

George E. Moore also discovered the use of fluorescent and radioactive materials to diagnose and localize brain tumors, was a pioneer in the use of chemotherapy to treat breast cancer, and developed techniques for growing tumor cells in a laboratory.

When Moore did his first studies of tobacco chewing in the 1950s, there was little strong evidence linking smoking and lung cancer and virtually none tying tobacco to other cancers.

In a seminal 1954 paper, Moore and colleagues from Roswell Park and the University of Minnesota reported on 40 men who suffered from oral cancer. They found that 26 of them had chewed tobacco, most for 15 years or longer. The paper presented the first evidence that chewing tobacco could be as lethal as smoking it.

Extending their studies, they also found that many people who chewed but did not yet have mouth cancer had gum irritation and leukoplasia -- white spots or patches on the interior of the mouth that are often a forerunner of cancer.

His discoveries put Moore on the leading edge of tobacco research for more than 15 years, but it was hard work because of the efforts of tobacco companies. When he tried to procure tobacco seedlings so he could grow his own plants, for example, he was unsuccessful until the husband of a woman he had treated for breast cancer provided some.

In his later life, he was pessimistic about his effort.

"With all of our scientific things, working as hard as we did, I don't think we influenced smoking very much," he told the Denver Post. "I think it became a socially accepted thing not to smoke, and that did more to change smoking habits than all of our scientific things."

George Eugene Moore was born Feb. 22, 1920, in Minneapolis. He attended the University of Minnesota, receiving his medical degree in 1947 and a doctorate in surgery in 1950.

He spent his early career at the University of Minnesota Medical School and at age 32 was named head of Roswell Park, then a struggling research institute with two aging buildings.

By the time he left in 1967, the institute, now known as the Roswell Park Cancer Institute, had grown to cover seven city blocks.

"He was a role model for oncologists and a highly successful administrator," said Dr. Donald L. Trump, current president and chief executive of the institute.

Moore left the institute when he was appointed director of public health research for the state of New York. He held the post until 1973, when he moved to Denver to join the University of Colorado School of Medicine. He spent the rest of his career there.

When Moore began his research, the primary treatment for breast cancer was surgical removal of the tumor. In the early 1960s, working with Dr. Rudolph Noer of the University of Louisville, Moore began supplementing surgery with the chemotherapeutic drug thiotepa.

They found that the drug could prevent or delay the recurrence of tumors in many patients. Unfortunately, it also triggered premature menopause; the drug gave way to more effective agents. But their study was among the first to show that chemotherapy could be useful in treating breast tumors.

Moore also developed chemical solutions that could be used to grow tumor cells in a laboratory, refusing to patent the technique so that it could be widely used. In the basement of his Denver office were nearly 1,000 such tumor lines, some of which had been kept alive 20 to 30 years. He called them "patients in a bottle."

Moore had a variety of interests outside oncology. He dabbled in metalworking, creating a 7-foot-tall sculpture of the cross-section of a cell that he displayed in his frontyard.

He also studied the geology of Colorado and was a past president of the Colorado Mineral Society.

He met his wife of 63 years, the former Lorraine P. Hammell, while hitchhiking to an airport outside Minneapolis to take flying lessons.

In addition to his wife, he is survived by two sons, Allan of Acton, Mass., and Donald of Conifer; three daughters, Cathy of Tucson, Laurie of Davis, Calif., and Linda of Golden, Colo.; two brothers, John of Minneapolis and Robert of San Jose; a sister, Elizabeth Severson of Minneapolis; eight grandchildren; and three great-grandchildren.

Mouth cancer checks DO happen, say dentists

6/23/2008
London, England
staff
Dentistry.uk.co A report revealing an alarming number of dental patients going without mouth cancer checks has prompted a tide of protest from dentists throughout the UK. The survey revealed that 71% of people said their dentist had never checked them for the condition. And 87% said their dentist had never even spoken to them about it.

Dr Nigel Carter, chief executive of the British Dental Health Foundation (BDHF), said: ‘Mouth cancer is a very serious condition.

‘It kills more than cervical cancer and testicular cancer combined, and yet a staggering 23% of people have never even heard of it.

‘The problem here appears to be twofold. First, not enough dentists are carrying out the checks, and second, those that do carry them out are failing to communicate this to their patients, missing a perfect opportunity to educate them on the dangers of mouth cancer.

‘NHS dentists are expected to carry out dental check-ups in a very short space of time, and it appears that many do not feel they have the time to carry out this important activity.'

The National Mouth Cancer Survey questioned 500 adults across 10 UK cities in April 2008 and was coducted by the BDHF and Medicash.

However, Mr Gill, a partner at Dean Road Dental Practice in South Shields, said: ‘It is something that is done, but not said.

‘When having a good look around the mouth, we look for these things. It is what we do. It is part of our job.'

Mr Gill has only come across three cases of mouth cancer in the 15 years he has been qualified.

He added: ‘It is not something you see often, but it is on the increase due to alcohol and smoking, and that is a concern. We check every patient, full stop.'

Dr Amarjit Gill, who works at a practice in Nottingham, said: ‘I'm sure dentists are checking, but maybe just not telling the patient.

‘The important thing for patients is to feel empowered and ask if they are worried about anything.

‘When you use the word 'cancer' with people, it sends shockwaves.'

Dr Gill said all his patients knew he checked for the disease and made them aware of it.

Mouth cancer kills one in two people that develop the condition but with early detection survival chances increase to nine out of ten.

Dentists are trained to spot the early signs of mouth cancer that can include ulcers that do not heal, lumps and red or white patches in the mouth.

Self-examination can also be beneficial.

Treatment of Patients with Clinically Lymph Node-negative Squamous Cell Carcinoma of the Oral Cavity

6/24/2008 Seoul, South Korea Won Il Jang et al.

Japanese Journal of Clinical Oncology 2008 38(6):395-401 Objective:
To evaluate treatment outcome and to determine optimal treatment strategy for patients with clinically lymph node-negative (N0) oral cavity squamous cell carcinoma (SCC).

Methods:
Two hundred and twenty-seven patients with oral cavity SCC received radiotherapy with curative intent. We retrospectively analyzed 69 patients with clinically N0 disease. Forty-three patients were treated with surgery followed by radiotherapy (S+EBRT) and 26 with radiotherapy alone (EBRT). The median doses administered were 63.0 Gy for S+EBRT and 70.2 Gy for EBRT.

Results:
The rates of occult metastasis were 60% for T1, 69% for T2, 100% for T3 and 39% for T4, respectively, among patients who underwent neck dissection. A contralateral occult metastasis occurred only in two patients. The median follow-up was 39 months (range, 6–170 months). The 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and regional control (RC) rates for all patients were 56, 50, 66 and 79%, respectively. The 5-year OS, DFS, LC and RC rates were 67/39% (P < 0.01), 66/24% (P < 0.01), 87/30% (P < 0.01) and 73/89% (P = 0.11) for S+EBRT/EBRT, respectively.

Conclusions:
The risk for occult neck metastasis is high in patients with oral cavity SCC; therefore, elective neck treatment should be considered. Excellent RC for subclinical disease can be achieved with radiotherapy alone. However, external beam radiotherapy alone to primary tumor resulted in poor LC and combined treatment with surgery and radiotherapy appeared to be a better treatment strategy.

Authors:
Won Il Jang1, Hong-Gyun Wu1,4,5, Charn Il Park1,4,5, Kwang Hyun Kim2, Myoung-Whun Sung2, Myung-Jin Kim3, Pill-Hoon Choung3, Jong-Ho Lee3 and Jin-Yong Choi3

Authors affiliations:
1 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul
2 Department of Otolaryngology and Head and Neck Surgery, Seoul National University College of Medicine, Seoul
3 Department of Oral and Maxillofacial Surgery, Seoul National University College of Dentistry, Seoul
4 Cancer Research Institute, Seoul National University College of Medicine, Seoul
5 Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea

Researchers from University of Minnesota publish findings in oral cancer

6/25/2008
Minneapolis, MN
staff
NewsRX (www.newsrx.com) According to a study from the United States, "Whole human saliva possesses tremendous potential in clinical diagnostics, particularly for conditions within the oral cavity such as oral cancer. Although many have studied the soluble fraction of whole saliva, few have taken advantage of the diagnostic potential of the cells present in saliva, and none have taken advantage of proteomics capabilities for their study."

"We report on a novel proteomics method with which we characterized for the first time cells contained in whole saliva from patients diagnosed with oral squamous cell carcinoma. Our method uses three dimensions of peptide fractionation, combining the following steps: preparative IEF using free flow electrophoresis, strong cation exchange step gradient chromatography, and microcapillary reverse-phase liquid chromatography. We determined that the whole saliva samples contained enough cells, mostly exfoliated epithelial cells, providing adequate amounts of total protein for proteomics analysis. From a mixture of four oral cancer patient samples, the analysis resulted in a catalogue of over 1000 human proteins, each identified from at least two peptides, including numerous proteins with a role in oral squamous cell carcinoma signaling and tumorigenesis pathways. Additionally proteins from over 30 different bacteria were identified, some of which putatively contribute to cancer development. The combination of preparative IEF followed by strong cation exchange chromatography effectively fractionated the complex peptide mixtures despite the closely related physiochemical peptide properties of these separations (pI and solution phase charge, respectively). Furthermore compared with our two-step method combining preparative IEF and reverse-phase liquid chromatography, our three-step method identified significantly more cellular proteins while retaining higher confidence protein identification enabled by peptide pi information gained through IEF," wrote H.W. Xie and colleagues, University of Minnesota.

The researchers concluded: "Thus, for detecting salivary markers of oral cancer and possibly other conditions of the oral cavity, the results confirm both the potential of analyzing the cells in whole saliva and doing so with our proteomics method."

Smokeless tobacco ups oral cancer risk 80 pct - WHO

Smokeless tobacco ups oral cancer risk 80 pct - WHO

Chewing tobacco and snuff are less dangerous than cigarettes but the smokeless products still raise the risk of oral cancer by 80 percent, the World Health Organisation's cancer agency said on Tuesday.

The review of 11 studies worldwide showed people who chewed tobacco and used snuff also had a 60 percent higher risk of oesophagus and pancreatic cancer.

The researchers sought to quantify the risk of smokeless tobacco after a number of studies differed on just how dangerous the products were, said Paolo Boffetta, an epidemiologist at the WHO's International Agency for Research on Cancer.

"What we did was try to quantify the burden of smokeless cancer," he said in a telephone interview. "This has never been attempted in such a systematic way before."

The researchers, who published their findings in Lancet Oncology, did this by looking at population-wide studies and trials of both humans and animals.

They found frequency of use varies greatly both across and within countries, depending on sex, age, ethnic origin and economic background, and were highest in the United States, Sweden and India.

They also found that while snuff and chew were less dangerous than smoking because they were not linked to lung cancer, getting cigarette users to switch was not good public policy.

"If all smokers did this there would be a net benefit," Boffetta said. "The point is we don't know whether this would happen and there is no data to suggest these smokers would stop or switch."