surgery

Neoadjuvant chemo does not improve oral cancer survival rates

Source: www.drbicuspid.com
Author: DrBicuspid Staff

Patients with advanced resectable oral squamous cell carcinoma (OSCC) who undergo surgery do not benefit from improved survival after induction with docetaxel, cisplatin, and fluorouracil (TPF), according to a new study (Journal of Clinical Oncology, November 5, 2012). Study author Zhi-yuan Zhang, MD, PhD, from Shanghai Jiao Tong University School of Medicine, and colleagues assessed 256 patients with resectable locally advanced OSCC.

A total of 222 patients completed the full treatment protocol. They received two cycles of TPF induction chemotherapy (75 mg/m2 of docetaxel on day 1, 75 mg/m2 of cisplatin on day 1, and 750 mg/m2 of fluorouracil on days 1 to 5) followed by radical surgery and postoperative radiotherapy versus upfront radical surgery and postoperative radiotherapy.

The primary end point was overall survival. Secondary end points included local control and safety.

After a median follow-up of 30 months, there was no significant difference in overall survival or disease-free survival between patients treated with or without TPF induction, the study authors noted. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response had superior overall survival and locoregional and distant control.

“Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with upfront surgery in patients with resectable stage III or IVA OSCC,” the authors concluded.

The lack of survival benefit indicates that TPF induction chemotherapy without selection could not benefit OSCC patients in general, Dr. Zhang told Reuters Health in a news story.

“On the other hand, superior outcomes are seen in responders, as assessed both by clinical and pathologic responses,” he said. “Therefore, induction chemotherapy is likely to be effective for biologically distinct subgroups, and biomarker development might lead to identification of patients whose tumors are likely to respond to a particular treatment.”

November, 2012|Oral Cancer News|

Interim results from CEL-SCI’s Multikine Phase III study on head and neck cancer

Source: www.news-medical.net

CEL-SCI Corporation announced today that an interim review of the safety data from its open label, randomized, controlled, pivotal Phase III study of Multikine (Leukocyte Interleukin, Injection) investigational immunotherapy by an Independent Data Monitoring Committee (IDMC) raised no safety concerns. The IDMC also indicated that no safety signals were found that would call into question the benefit/risk of continuing the study. CEL-SCI considers the results of the IDMC review to be important since studies have shown that up to 30% of Phase III trials fail due to safety considerations and the IDMC’s safety findings from this interim review were similar to those reported by investigators during CEL-SCI’s Phase I-II trials. Ultimately, the decision as to whether a drug is safe is made by the FDA based on an assessment of all of the data from a trial.

IDMCs are committees commonly used by sponsors of clinical trials to protect the interests of the patients in ongoing trials especially when the trials involve patients with life threatening diseases, and when, as in cancer clinical trials, they extend over long periods of time (3-5 years). The committee’s membership should include physicians and clinical trial scientists knowledgeable in the appropriate disciplines, including statistics. The CEL-SCI IDMC includes prominent physicians and scientists from major institutions in the USA and abroad who are key opinion leaders in head and neck cancer and who are knowledgeable in all of the disciplines related to CEL-SCI’s study, including statistics.

The Multikine Phase III study is enrolling patients with advanced primary, not yet treated, head and neck cancer on 3 continents around the world. The objective of the study is to demonstrate a statistically significant 10% improvement in overall survival of enrolled patients who are treated with Multikine plus Standard of Care (SOC) vs. subjects who are treated with SOC only. The universally accepted current standard of care for the patient population being enrolled in the CEL-SCI study is surgery plus radiation or surgery plus concurrent radiation and chemotherapy, dependent on the risk factors for recurrence found after surgery. Multikine treated patients receive 15 local injections of Multikine over a 3 week period prior to standard of care treatment. Multikine injections are administered in the area around the tumor and in the area of the adjacent lymphnodes since those two areas are where the tumor is most likely to recur. Multikine is intended to create an anti-tumor immune response to reduce local / regional tumor recurrence and thereby increase the survival of these patients.

Multikine is the first immunotherapeutic agent being developed as a potential first-line treatment for advanced primary head and neck cancer. If it were to be approved for use following completion of our clinical development program, Multikine would become an additional and different kind of therapy in the fight against cancer: one that employs our body’s natural ability to fight tumors.

Source: CEL-SCI Corporation

October, 2012|Oral Cancer News|

Blacks with throat cancer get harsher therapy

Source: in.reuters.com
Author: Frederik Joelving

Blacks in the United States with throat cancer are more likely than whites to have surgery that leaves them unable to speak than to get gentler voice-preserving therapy, according to a study. Previous research has found a similar racial disparity in breast cancer treatment, with blacks more often having the entire breast removed instead of just the cancerous lumps. It’s unclear why the disparity exists. But study leader Allen Chen, a radiation oncologist at University of California, Davis, said that poverty, less education and deep-rooted historical biases could all be at work.

“There could be an underlying distrust among African Americans where they feel anything less than surgery might be considered quote-unquote experimental,” Chen told Reuters Health.

He referenced the Tuskegee experiment, conducted by the U.S. government from the 1930s into the 1970s, in which black patients with syphilis went untreated despite assurances to the contrary.

“That sort of distrust needs to be addressed or alleviated,” Chen said, because voice-preserving treatment for throat cancer, based on radiation and drug therapy, is now the standard.

His study, published in the Archives of Otolaryngology – Head & Neck Surgery, is based on data from a US cancer registry including nearly 5,400 cases of laryngeal cancer between 1991 and 2008.

About 80 percent of whites had voice-preserving treatment, while the rest had their voice box surgically removed – the traditional approach. Among blacks, 75 percent had the gentler therapy. While that’s only a five-percent difference, “I think that’s a gap that needs to be narrowed,” Chen added.

The racial disparity remained after researchers accounted for age, sex and how advanced patients’ tumors were, and it didn’t disappear in the more recent half of the study, either. However, there was no significant gap between whites and Hispanics or Asians. The study didn’t look at income or education, which might explain some of the difference. It’s also possible that more blacks lived in areas without access to the resources involved in voice-preserving therapy, which requires cooperation between doctors with different specialties.

While the gentler therapy might be just as effective as surgery, an operation does have the advantage of being over at once, whereas it takes several weeks of treatment for drugs and radiation to work.

But if it’s a question of people believing treatment other than surgery is experimental, he added, “That perception needs to be changed.”

Source: Reporting from New York by Frederik Joelving at Reuters Health; editing by Elaine Lies and Bob Tourtellotte

Facing the facts: HPV-associated head and neck cancers get a second look

Source: www.curetoday.com
Author: Charlotte Huff

Kevin Pruyne knew he didn’t fit the stereotype of a hard drinker or heavy smoker who one day develops an oral cancer.

The 52-year-old mechanic had been working a three-week stint in a remote section of northern Alaska, repairing trucks on an oil field, when he noticed a hard lump beneath his jaw while shaving. For nearly three months, as Pruyne was prescribed antibiotics for a possible infection and then later shuttled between physician specialists, he kept hearing the same thing: the lump could not be cancer.

Pruyne only occasionally consumed alcohol and had never smoked. His wife, Kathy, began researching her husband’s symptoms, which included repetitive throat clearing, a nagging sensation that something was lodged in his throat and ringing in his ears. And the lump, which looked like the top half of an egg, felt solid to the touch.

This wasn’t some inflamed lymph node from a lingering head cold, Kathy Pruyne says. “He had every symptom [of cancer], but nobody would listen to me.”

Pruyne received a diagnosis of stage 4 oral cancer, which started with a tumor at the base of his tongue. He had already begun chemotherapy when he learned that researchers had discovered an association between the human papillomavirus (HPV) and increasing rates of oropharyngeal cancers. He asked that his tissue be tested; the results came back positive. Pruyne says he wanted to know whether his cancer was caused by HPV because “the prognosis is considerably better with HPV-positive cancer.” He adds he “wanted to hear that there was a better chance of a cure.”

An Explosion of Cases

For researchers and clinicians alike, determining appropriate treatment has taken on new urgency: HPV-positive oropharyngeal malignancies—most typically found on the tonsils or at the base of the tongue—increased 225 percent from 1988 to 2004. If current trends continue, HPV-positive oral cancer cases could soon surpass cervical cancer diagnoses, according to a 2011 study published in the Journal of Clinical Oncology.

As researchers have revisited data from prior oral cancer treatment studies, they’re realizing that patients with HPV-positive tumors respond better to chemotherapy and radiation. One study, which retrospectively analyzed treatment outcomes for stage 3 and stage 4 oropharyngeal patients based on their HPV status, found that the three-year overall survival rate was 82.4 percent in patients with HPV-positive tumors. Among those who tested negative, the three-year overall survival rate was 57.1 percent, according to the findings published in 2010 in The New England Journal of Medicine.

With that in mind, research trials are being launched to determine whether treatment can be modified in some way or even dialed back. The goal? To achieve the same survival with fewer of the swallowing difficulties, taste problems and other debilitating side effects.

“For a subset of patients, we’ve actually achieved a pretty high cure rate,” says James Rocco, MD, PhD, a head and neck surgeon at Massachusetts Eye and Ear Infirmary, and director of head and neck cancer research at Massachusetts General Hospital. “And the question is: Can we maintain that cure and reduce some of the major side effects of treatment?”

But researchers and oncologists have only just begun to understand HPV-positive malignancies. “It’s very clear that HPV-positive oropharyngeal cancer is a completely different entity from HPV-negative,” says Stephen Liu, MD, a head and neck cancer specialist, and an assistant professor of medicine at the University of Southern California.

“We think that it’s going to impact treatment in the future,” Liu adds. But, he stresses, outside of a clinical trial, he “would really discourage anyone from receiving less treatment because their tumor is HPV-positive.”

Identifying the Virus

Traditionally, tobacco and alcohol use have been the primary culprits for triggering cancers in the oropharynx and nearby areas of the mouth, as well as other structures in the throat, such as the larynx. Each year, nearly 40,000 Americans develop cancer of the oral cavity or pharynx. Men are more than twice as likely to receive a diagnosis.

But, until recent years, not someone like David Hastings. The certified public accountant was 58 years old, a lean cyclist who rode some 100 miles each week, when he learned six years ago that he had stage 4 oropharyngeal cancer located at the base of his tongue. Clinicians at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., also were puzzled, as the Gulfport resident tells it. “They said the typical oral cancer patient is a man in his 60s or 70s who sits in a bar all day and drinks and smokes.”

The association with HPV emerged from a perplexing conundrum, says Kian Ang, MD, PhD, a professor in the department of radiation oncology at M.D. Anderson Cancer Center in Houston. As cigarette smoking has declined in recent decades, so have head and neck cancers, with the exception of tumors in the oropharynx. (The region encompasses the middle section of the throat, along with the back portion of the tongue, the soft palate and the tonsils.) That statistical anomaly, Ang says, “gave us the first clue that something else might be going on.”

 

Starting with a pivotal study published in 2000, researchers began honing in on the role of HPV. Of the 150-plus strains in the HPV family, more than 40 are believed to be transmitted through sexual contact, including anal, genital and oral, according to the National Cancer Institute. The body’s immune system typically eradicates the viruses in a few years before any symptoms emerge (but, in some cases, the cells remain molecularly altered forever). Several of the HPV strains to date, most frequently HPV type 16, have been linked to oral malignancies.

Increasingly, HPV-16 has become a major player in those oral malignancies, according to last year’s Journal of Clinical Oncology study, which projected an explosion in cases in the decades to come.

When researchers studied 271 tissue samples in previously diagnosed patients, HPV prevalence was identified in only 16.3 percent of those collected between 1984 and 1989. Between 2000 and 2004, 72.7 percent of specimens tested positive, a trend that also perhaps correlates with population-wide increases in oral sex, the researchers wrote.

The analysis also highlighted survival differences. If tumors tested HPV-positive, the median survival was nearly 11 years versus 1.6 years for people whose tumors didn’t carry the virus.

Some of the strides in oral cancer treatment that physicians thought they were achieving can at least be partially explained by the emergence of a less aggressive form of cancer, Ang says. “The other part of the improvement,” he says, “is really due to the addition of chemotherapy and the use of high-precision radiation.”

Multifaceted Treatment

Cancers located in the tonsils or at the base of the tongue can sometimes spread undetected, not becoming visible until they’ve reached the nearby lymph nodes. Some early symptoms include swallowing difficulties or a sudden change or hoarseness in the voice. Like Pruyne, Hastings first became concerned when he felt a mysterious lump while shaving. “Totally painless, no sore throat—nothing,” he says.

Oropharyngeal tumors can be classified as stage 3 or 4 but still be considered localized, as long as they have not spread beyond lymph nodes and structures in the head and neck. Pruyne, whose cancer had migrated to numerous nodes on his neck’s right side, recalls how his oncologist hurried out of the room when his imaging test results became available.

The doctor had already warned Pruyne that he could offer relatively little help if the cancer had spread to his chest. “When he came back up, he was visibly relieved,” Pruyne recalls. “And he said, ‘Your lungs are clear.’”

To thwart oropharyngeal malignancies, cancer specialists may incorporate a mix of treatments, including surgery, radiation and chemotherapy, depending upon the location and the aggressiveness of the tumor involved. Ang estimates that only about one-third of patients will undergo surgery. If the tumor can be removed and there’s no evidence that it’s spread to lymph nodes, radiation may not be needed, he says.

 

But if there’s any concern, patients may receive six weeks of radiation for smaller tumors and seven weeks for larger ones, Ang says. Intensity-modulated radiation therapy (IMRT) is used because it better targets the radiation and thus can limit damage to the salivary glands, reducing dry mouth, as well as damage to other normal tissues, Ang says.

For larger and more aggressive tumors, adding chemotherapy to radiation therapy has been shown to extend survival. One meta-analysis published last year, based on 87 studies involving more than 16,000 patients, analyzed results by tumor location. Researchers found that the combination approach increased five-year overall survival by 8.1 percent in oropharyngeal patients compared with those who didn’t receive any chemotherapy.

The chemotherapy is believed to boost the effectiveness of the radiation, but at a cost—amplified side effects for the patient. The list of potential side effects is lengthy, with so many vulnerable structures and nerves packed into the head and neck area, Liu says. Patients can develop ulcers in their mouth and down their throat, he says. Their salivary glands can generate thick secretions that make it difficult to swallow and to eat.

“The ability to taste, to speak, to salivate,” says Liu, ticking off several more. “Dry mouth. These things can often be permanent. It’s a necessary evil right now because we do what we need to do to cure the cancer.”

Pruyne received two cycles of a cisplatin-based protocol that also included Taxotere (docetaxel) and 5-FU (fluorouracil). Then he started the biologic agent Erbitux (cetuximab) along with hefty doses of IMRT, delivered twice daily for six weeks.

Pruyne’s oncologist warned him that the treatment would be difficult, and it was. He endured radiation burns around the right side of his neck and had to use a feeding tube for two months.

Dialing Back

Although radiation and chemotherapy can be difficult, some patients prefer to take that route, rather than run the risks of surgery, Rocco says. “For advanced local disease, removing the back of the tongue or the soft palate has huge consequences for people,” Rocco says. “They can’t eat. They don’t speak so well.”

But given that patients with HPV-positive tumors are typically diagnosed at a younger age, with potentially decades ahead of them to cope with long-term side effects, the aggressiveness of today’s chemotherapy and radiation regimens are also questionable, he says.

Clinical trials are recruiting patients to answer a question that’s relatively rare in cancer: Can treatment be ramped down? One closely watched phase 3 trial will assess whether Erbitux works as well in HPV-positive patients as the long-standing cisplatin-based chemotherapy regimen.

Cisplatin has been one of the standard drugs used in head and neck cancer, but it’s “very toxic,” says Andy Trotti III, MD, the study’s principal investigator and director of radiation oncology clinical research at Moffitt Cancer Center. The platinum-based drug can impact kidney function and sometimes damage hearing, among other side effects, he says.

Erbitux, which targets the epidermal growth factor receptor (EGFR), primarily affects the skin, Trotti says. In the phase 3 trial, now recruiting HPV-positive patients, the five-year overall survival of patients on Erbitux will be compared with those taking cisplatin. Both groups will receive IMRT.

Another ongoing trial is looking at whether the IMRT regimen can be shortened from six to five weeks, thereby delivering a lower dose of radiation in HPV-positive patients. The patients enrolled in that phase 2 trial, who also will receive cisplatin,  paclitaxel and Erbitux, will be followed for two years.

The study represents a “first step” toward learning whether less radiation can be safely prescribed for HPV-positive patients, Liu says. Since radiation’s effects are cumulative, the extra week of radiation adds “a significant amount of toxicity.”

A New Era in Treatment

Meanwhile, the impact of HPV status on surgical decisions appears to be the subject of some unresolved debate. Given that HPV-positive oropharyngeal malignancies respond well to chemotherapy and radiation, Trotti says, “there has been a real trend away from surgery.”

But new surgical techniques are providing other options for HPV-positive patients who might prefer to limit the long-term side effects of chemotherapy and radiation, says Bert O’Malley, Jr., MD, chairman of the department of otorhinolaryngology of the University of Pennsylvania Health System.

Along with a physician colleague, O’Malley has developed a robotic surgery protocol called TransOral Robotic Surgery. With the assistance of tiny robotic arms and three-dimensional cameras, O’Malley operates through the patient’s mouth, enabling him to remove difficult-to-reach tumors.

A surgery that previously required between six and 16 hours might only take two, he says. Also the approach results in less scarring and fewer surgical complications than the traditional surgery, which may require the jaw to be split, he says.

It’s a new era in HPV-positive treatment, Rocco says. To make his point, he tells of a patient who recently walked in asking to be referred for robotic surgery. The gold standard is still to wait for clinical trial results, but that could take five-plus years, he adds.

HPV-positive patients are frequently “savvy young professionals in the prime of life,” who sort through the latest research online, Rocco points out.

“There are people who are risk-takers,” he says. “They’ll look at the data, and they’ll make a decision, weighing cure and long-term side effects.”

Despite the rigors of treatment, Pruyne was able to resume his job near the Arctic Circle within a few months. He hopes to soon be telling a tale similar to Hastings’, who returned to his biking routine about a year after wrapping up treatment.

Hastings still copes with dry mouth and a reduced ability to taste. But the last time he visited Moffitt for an annual checkup, it felt more like a social call. After some chatting, he quips: “They said, ‘Get out of here. We need to spend more time with people who are sick.’”

 

Oral sex may cause more oral cancer than smoking in men, researchers say

Source: www.bloomberg.com
Author: Robert Langreth

A virus spread by oral sex may cause more cases of throat cancer in men than smoking, a finding that spurred calls for a new large-scale test of a drug used against the infection. Researchers examined 271 throat-tumor samples collected over 20 years ending in 2004 and found that the percentage of oral cancer linked to the human papillomavirus, or HPV, surged to 72 percent from about 16 percent, according to a report released yesterday in the Journal of Clinical Oncology. By 2020, the virus-linked throat tumors — which mostly affected men — will become more common than HPV-caused cervical cancer, the report found.

HPV is known for infecting genitals. The finding that it can spread to the throat and cause cancer may increase pressure on Merck & Co., the second-largest U.S. drugmaker, to conduct large-scale trials to see if its vaccine Gardasil, which wards off cervical cancer in women, also prevents HPV throat infections.

“The burden of cancer caused by HPV is going to shift from women to men in this decade,” Maura Gillison, an oncologist at Ohio State University and study senior author, said in a telephone interview. “What we believe is happening is that the number of sexual partners and exposure to HPV has risen over that same time period.”

Gillison said she worked with researchers at Whitehouse Station, New Jersey-based Merck several years ago to design a study in men. After Merck acquired Schering-Plough Corp. in 2009, though, the trial “was canceled,” she said.

No Further Study
Pamela Eisele, a spokeswoman for Merck, said the company decided not to move ahead with a big oral cancer study “due to competing research and business priorities.” GlaxoSmithKline Plc (GSK) has “no plans” to study the company’s competing vaccine Cervarix outside of cervical cancer, Jennifer Armstrong, a company spokeswoman, said in an e-mail.

Gardasil is approved for preventing cervical, vaginal and anal cancers and genital warts, and is recommended for girls and women ages 9 through 26. It is also approved for preventing genital warts and anal cancer in boys and young men of the same ages. Glaxo’s Cervarix is approved for preventing cervical cancer in females ages 9 through 25.

Both vaccines target the HPV strain linked to oral cancer, Gillison said.

HPV-linked throat cancers, or orophyaryngeal cancer, are increasing so rapidly that by 2020 there will be 8,700 U.S. cases, with 7,400 cases in men, versus 7,700 cases of cervical cancer, the study said. Male cases alone will outnumber cervical cancer cases soon after 2020, Gillison said. The Ohio State study is based on tumor samples from several U.S. states.

HPV Infections
Roughly 20 million Americans have genital HPV infections, according to the Atlanta-based Centers for Disease Control and Prevention. At least half of sexually active women and men get it at some point in their lives, the CDC says. Most of the time it doesn’t cause health problems.

Until recently, head and neck cancer mainly occurred in older patients and was associated with tobacco and alcohol use. The HPV-linked head and neck cancers, usually of the tonsils, palate or tongue, hit men their 30s, 40s, and 50s, Gillison said. It is unclear why women are affected much less often than men, she said.

The decline in HPV-negative oral cancers mirrors the decline of smoking in the U.S., the study said.

Treatment involving chemotherapy, radiation and sometimes surgery, “is very nasty,” said Gillison. “It can leave people with permanent physical disfigurement, difficulty with speech and swallowing and poor dental health.”

Research Effort
Gillison started researching the oral cancer epidemic more than a decade ago as a fellow at Johns Hopkins University. Another researcher told her about a report from Europe of a case of oral cancer that was HPV positive, she said.

“I started working on it immediately,” she said.

In a 2007 epidemiology study published in the New England Journal of Medicine, Gillison and her colleagues found that having a high number of oral or vaginal sex partners are risk factors for HPV-associated throat cancer. The cancer may also be spread by open-mouth kissing, Gillison said in the interview.

“Nobody paid attention to oral HPV infections until 2007,” she said. “We are about 15 years behind in the research” compared with the data on cervical cancer and HPV, she said.

An editorial accompanying the study concluded that trials to see whether vaccines prevent oral cancer “are needed, given that prevention through vaccination will almost certainly be the ultimate solution” to HPV-positive oral cancers.

A key step would be to perform a natural history study that would follow people over a number of years and track in more detail how HPV-oral infections lead to cancer. This could help inform how to design a vaccine trial, Gillison said.

Both vaccines target the HPV strain linked to oral cancer, Gillison said.

Study: Oral cancers take financial toll

Source: Dr.Biscuspid.com

April 26, 2012 — The cost of treating individuals with oral, orapharyngeal, and salivary gland cancers is significant, particularly for patients who undergo all three forms of treatment, according to a new study by Delta Dental of Michigan’s Research and Data Institute. And for many that is only the beginning of the financial impact of the disease.

The project, which involved Thomson Reuters, Delta Dental of Wisconsin, Vanderbilt University, and the University of Illinois at Chicago College of Dentistry, began in March 2010. It is the first retrospective data analysis of a large number of head and neck cancer patients in the U.S. analyzing direct and indirect costs and comparing those costs to a matched comparison group, according to the authors (Head Neck Onc, April 26, 2012).

Using data from the 2004-2008 Thomson Reuters MarketScan Databases: Commercial Claims and Encounters Database, Medicare Supplemental and Coordination of Benefits Database, Medicaid Multi-State Database, and the Health Productivity and Management Database, the researchers retrospectively analyzed claims data of 6,812 OC/OP/SG patients with employer-sponsored health insurance, Medicare, or Medicaid benefits.

They found that, on average, total annual healthcare spending during the year following diagnosis was $79,151, compared with $7,419 in a group comprising similar patients without these cancers. They also found that the average cost of care almost doubled when patients received all three types of treatment: surgery, radiation, and chemotherapy.

Healthcare costs were higher for oral cancer patients with commercial insurance ($71,732, n = 3,918), Medicare ($35,890, n = 2,303), and Medicaid ($44,541, n = 585) than the comparison group (all p < 0.01). Commercially-insured employees with cancer (n = 281) had 44.9 more short-term disability days than comparison employees (p < 0.01), the study found. Multimodality treatment was twice the cost of single modality therapy. Those patients receiving all three treatments (surgery, radiation, and chemotherapy) had the highest costs of care, from $96,520 in the Medicare population to $153,892 in the commercial population.

“The results of this research are significant in helping us to fully understand the cost burden of these three particular head and neck cancers on patients and health care providers,” stated Jed Jacobson, DDS, MS, MPH, chief science officer at Delta Dental and a lead contributor to the study, in a press release. “To our knowledge, this is the first study of its kind.”

One of the big problems with oral cancer is that it is uncovered so late in the disease that the chances of survival are terrible, he added.

“So the key is early detection and diagnosis,” Dr. Jacobson said. “In the last decade, we have seen a flurry of activity in new science and technology with the promise of being able to find it earlier. The problem is, should I as a purchaser of healthcare buy this benefit? The answer is often return on investment: if I spend a dollar on this new technology, do I save anything relative to finding the cancer earlier? So we need to know what oral cancer costs.”

Social, psychological, economic impact

The project examined other factors also, including:

  • Indirect costs associated with these cancers from diagnosis, treatment, and recovery, such as absenteeism, worker productivity, and the disabling and disfiguring side effects of treatment
  • The cost burden of oral cancer on taxpayers who fund Medicaid and Medicare
  • The comparative value of preventive care for these oral cancers versus treatment

“Most oral cancers require costly and disfiguring medical intervention, and even then the five-year survival rate is approximately just 60%,” Dr. Jacobson said. “Yet when the cancer is detected early, the survival rate increases to 83%. This study allows us to get a better handle on the cost impact these diseases have and how we can combat them better.”

Head and neck cancers have always piqued the interest of health care providers, patients, and insurers because of the high-morbidity, high cost of care, and high-mortality rates associated with them. Yet, it has largely remained an unexplored area when it comes to research and backing up these conclusions.

“The actual study of the social, psychological, and economic impacts of these cancers has been understudied,” states Dr. Joel Epstein, former professor of oral medicine and diagnostic sciences at the University of Illinois in Chicago, now adjunct professor, director of oral medicine at City of Hope in Duarte, CA. “These are the reasons we decided to conduct this important research and be able to shed more light on the cost burden of treating head and neck cancer.”

By including screening as part of regular dental exams, dentists and hygienists have the opportunity to detect these cancers early, decreasing morbidity and mortality, the study authors noted. In addition, educational programs to raise awareness among health care providers and programs instructing individuals on self-examination may result in earlier detection and greatly reduce the high cost and mortality of oral and head and neck cancers.

“The information [in this study] will be a great asset in determining the cost-effectiveness of any new technologies and early detection systems that could potentially help decrease costs, and more importantly, lower the mortality rate of these cancers down the road,” Dr. Jacobson concluded.

However, while the findings of this study are important, it does not address the additional financial burden many oral cancer survivors face after treatment, noted Brian Hill, executive director of the Oral Cancer Foundation.

“If you look at the financial consequences in this economy, by not finding this disease early, the morbidity associated with treatments is significant,” he told DrBicuspid.com. “But also, treatment is just the beginning of the financial cascade of events. There are larger consequences to the economy. It isn’t just about survival, but other long-term consequences insurance wise, personally, and at the government level also due to long-term disability.”

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

Oral gel contains cancer-preventing compounds derived from black raspberries

Source: www.dentistryiq.com
Author: Maria Perno Goldie, RDH, MS, with the assistance of Allison Walker

Maria Perno Goldie (MPG): I had the opportunity to interview Dr. Susan Mallery, who is a humble as she is intelligent. I had the assistance of Allison Walker, a freelance journalist who has been involved in dental publishing for more than 20 years.

Dr. Susan Mallery (SM) is a Professor in the Division of Oral Surgery, Oral Pathology, and Anesthesiology at The Ohio State University, College of Dentistry, in Columbus, Ohio. Her research interests include oral cancer initiation, AIDS-related oral cancer and chemoprevention. Dr. Mallery has published articles in journals such as Cancer Research, Cancer Prevention Research, Molecular Pharmaceutics, Carcinogenesis and Clinical Cancer Research, to name a few.

She graduated from The Ohio State University with her DDS and later returned to receive her oral pathology specialty training and a PhD in Pathology. Dr. Mallery is licensed by the Ohio State Dental Board and board certified by the American Board of Oral Pathology and American Academy of Oral Pathology. She belongs to the American Academy of Oral Pathology, American Board of Oral Pathology, American Association for Cancer Research, and is a Fellow of the American Association for the Advancement of Science. She is a consultant at The Ohio State University and James Cancer hospitals.

MPG: Oral squamous cell carcinoma (OSCC) will be diagnosed in more than 36,000 Americans this year and has a particularly high mortality rate—as it will kill approximately 8,000 patients this year. As excisional surgery is the primary treatment for OSCC—even those patients who are cured suffer loss of tissues critical for esthetics, speech and eating. Due to OSCC’s high rates of morbidity and mortality and its high socio-economic impact, a strategy to prevent progression of precancerous oral lesions to OSCC is more appealing.

Currently, precancerous oral lesions are surgically removed—with either a blade or laser—and the tissues evaluated microscopically. Discouragingly, approximately 30% of lesions that are completely removed as confirmed by microscopic evaluation recur and some progress to OSCC. Dr. Mallery has dedicated her nearly 30-year career to studying new strategies to preventing oral cancer. Her research has been supported by funding from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and The Ohio State University (OSU) Center for Clinical and Translational Science. It is also funded by the Fanconi Anemia Research Fund, a grassroots organization whose mission is to find effective treatments and a cure for Fanconi anemia and to provide education and support services to affected families worldwide. Dr. Mallery stresses that she is a part of a team, and that the research is truly a team effort.

Fanconi anemia (FA) is one of the inherited anemias that leads to bone marrow failure (aplastic anemia). It is a recessive disorder: if both parents carry a defect (mutation) in the same FA gene, each of their children has a 25% chance of inheriting the defective gene from both parents. When this happens, the child will have FA. Fanconi anemia patients have an extremely high risk of developing squamous cell cancers in areas of the body in which cells normally reproduce rapidly, such as the oral cavity, esophagus, the gastrointestinal tract, the anus, and the vulva. FA patients may develop these cancers at a much earlier age than people without Fanconi anemia.

Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problems associated with FA, still must have regular examinations to watch for signs of cancer. Head and neck squamous cell carcinoma (HNSCC) is a significant threat for people with FA, regardless of bone marrow transplantation status. Not only is the incidence of HNSCC considerably higher than in the general population (500-700 times higher), patients with FA present with these types of cancers at a younger age than those without FA – the median age is 27 years. Regular screenings are critically important.

MPG: Dr. Mallery, you have been investigating a number of agents to identify new therapeutics that can suppress the conversion of pre-cancerous to cancerous cells (chemoprevention), in particular, anthocyanins. Can you explain this to us?

SM: Chemoprevention is a way to prevent or delay the development of cancer by taking medicines, vitamins, or other agents. My colleagues and I are using a bimodal approach. Our first breakthrough was the creation of an oral gel containing high concentrations of anthocyanins, powerful cancer-preventing compounds found in black raspberries. Study results showed that the gel, when applied to the mouth, selectively removed atypical epithelial cells for the population through either preprogrammed cell death (apoptosis) or causing terminal differentiation (making the protective keratin covering).

MPG: Can you explain the mechanism of action of these anthocyanins?

SM: As briefly mentioned above, anthocyanins—and likely other black raspberry (BRB) compounds—are capable of modulating epithelial cell growth by affecting intracellular signaling and gene expression. Also apparent from our pilot study was that some patients derived more benefit from gel application. These inter-patient differences prompted a later study to help identify the cause.

Analyses of saliva samples collected after BRB rinses were conducted to assess local pharmacokinetics and compare the capacities of three different BRB rinse formulations to provide sustained intraoral levels of anthocyanins. Not surprisingly, these studies showed that BRB metabolism was affected by three intraoral enzymatic components, i.e. (1) oral tissues, (2) saliva, and (3) oral bacteria (“microflora”).

As all three components affected BRB bioactivation and local retention, it is likely inter-patient differences in these three areas that contribute in large part to BRB gel responsiveness. We are currently conducting the logical extension study of the pilot trial, which entails inclusion of a gel-placebo and multicenter testing. Results to date have confirmed therapeutic efficacy is limited to the BRB gel formulation and not the placebo. More complex analyses—which assess the gel’s effect at the molecular level—are ongoing.

One of the largest challenges with oral cancer chemoprevention is to develop an effective, yet nontoxic strategy. Efficacy speaks for itself—the need for nontoxic is tied to the fact that many to most of these treatments will be necessary for the life of the patient. The lifelong need is tied to the fact that persons who develop precancerous oral lesions have genetic mutations in the cells that are key for future epithelial generations, i.e., epithelial stem cells. When stem cells divide (which is not very often), they make perfect copies of themselves. Consequently, if the stem cells are mutated, their daughter cells faithfully carry forward this mutation. Our BRB gel data imply that locally applied black raspberry constituents can re-direct appropriate epithelial cell growth by removing mutated cells from the overall cell population. Consistent with a food-based approach, no systemic or local toxicities occurred.

Local delivery allows for better therapeutic concentration at the site with fewer systemic side effects. With oral cancer chemoprevention given systemically, the liver, in first-pass metabolism, makes the agent less active than the parent compound. The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption that is generally related to the liver and gut wall. We must have a compliant patient population with local delivery, it is vital. In some cases the decision involves having multiple biopsies or applying a gel a number of times per day. Not having frequent biopsies can be a good motivator.

MPG: Dr. Mallery, you have been investigating alternatives to the surgical removal of pre-cancerous oral lesions. Can you explain what you have found in this area?

SM: We have turned our attention to identifying alternatives to the surgical removal of pre-cancerous lesions. However, we are not “there” yet. Close clinical follow up is critical. If we suspect a malignant lesion, we must first biopsy, and if it is an active lesion, place the gel to prevent recurrence.

MPG: Dr. Mallery went on to tell a story about her passion and her work in one of the studies. She related that one third of the patients in the pilot trial were “super” responders, lesions resolved clinically and histologically, and biochemical and molecular markers returned to normal after treatment. There was an intermediate group of about one third, and the last third did not respond in either a negative or positive way. The researchers wanted to determine what caused the “super” responders to react as they did. The study was done with normal, healthy people, and it was found that there is a large difference in variability in enzyme levels to recycle the product. Best responders bioactivate the product and keep it in place for a long time. Enzyme profiles are being done.

SM: Because BRB components alone are insufficient to regress some patients’ precancerous oral lesions, we have decided to introduce a second chemopreventive, the synthetic vitamin A compound, fenretinide. Fenretinide is a “bench” chemopreventive star capable of causing either differentiation or apoptosis in transformed epithelial cells. Previous fenretinide oral cancer chemoprevention trials, which relied on systemic fenretinide delivery, were unsuccessful. Although none of these studies assessed drug levels at the target site, the pill-based delivery format could not even achieve treatment-relevant blood levels. Furthermore, large systemic doses of fenretinide resulted in toxicities including night blindness and changes in blood lipid profiles.

The objective of this study was to enhance oral mucosal permeation of fenretinide by co-incorporation of propylene glycol (PG) and menthol in fenretinide/Eudragit RL PO mucoadhesive patches. Fenretinide is an extremely hydrophobic chemopreventive compound with poor tissue permeability. Co-incorporation PG or menthol in fenretinide/Eudragit RL PO patches led to significant ex vivo fenretinide permeation enhancement. Addition of PG above 2.5 wt% in the patch resulted in significant cellular swelling in the buccal mucosal tissues. These alterations were ameliorated by combining both enhancers and reducing the PG level.

After buccal administration of patches in rabbits, in vivo permeation of fenretinide across the oral mucosa was greater relative to permeation obtained from the enhancer-free patch. In vitro and in vivo release of fenretinide from the patch was not significantly increased by co-incorporation of permeation enhancers, indicating that mass transfer across the tissue, and not the patch, largely determined the permeation rate control in vivo. As a result of its improved permeation and its lack of deleterious local effects, the mucoadhesive fenretinide patch co-incorporated with 2.5 wt% PG + 5 wt% menthol represents an important step in the further preclinical evaluation of oral site-specific chemoprevention strategies with fenretinide.

Fenretinide was studied in pill form, where there was more drug in the blood versus at the site. There were also toxicity problems. My team and I always thought that fenretinide would be a good drug if delivered in a different manner.

I worked with Peter Larsen, DDS, Chair of Division, Oral Maxillofacial Surgeon, Gary Stoner, PhD, and Kashappa Goud Desai, PhD, in both trials. Steven P. Schwendeman, PhD, is a pharmaceutical chemist, Professor and Chair Department of Pharmaceutical Sciences, College of Pharmacy, at the University of Michigan. His lab developed the fenretinide patch with Kashappa-Goud Desai, PhD. Fenretinide is lipophillic, and they needed the formulation to be stable, for the patch to stick on the site, deliver drug, and allow the drug to penetrate in an aqueous environment into keratinized tissue. It is great science! These two researchers are involved with patent application for the fenretinide patch, to be placed on active or recently excised lesions.

A combination approach with these two chemotherapeutics may someday be achieved and they may be complementary or synergistic. They have different mechanisms of action and if delivered at the same time could be antagonistic. The dosing must be staggered, with initial application, and perhaps 12 hours later, delivery of the next drug. When the patch is applied to lesions, pharmacokinetic studies show no drug in the saliva. The hypothesis is for targeted delivery and uptake of fenretinide, followed by field coverage with the raspberry rinse. A published study stated that the objective was to develop fenretinide oral mucoadhesive patch formulations and to evaluate their in vitro and in vivo release performance for future site-specific chemoprevention of oral cancer. The gel was used topically at the site of the lesion or after excision.

Our goal is to create complementary oral cancer chemoprevention strategies that would permit targeted delivery directly to visible lesions as well as address the need for field coverage throughout the mouth. My colleagues and I are optimistic that optimized delivery formulations and dosing schedules for BRB and fenretinide will help make appreciable clinical progress. We aim to prevent cancerization, which is transformation of cells into cancer, or from a normal to a cancerous state.

The concept is that being exposed to toxins and metabolic enzymes can activate toxins and cause the mutated cells to become active. There is now a multi-centered NCI trial of the raspberry product in patients, based on the pilot study. There are two manuscripts, one published and one pharmacokinetic study in rabbits ready to be published. The patch is considered a device by the FDA and they must apply as an Investigational New Device (IND). It is a very safe drug.

MPG: Dr. Mallery, what is your advice about prevention of oral cancers?

SM: I recommend not using tobacco in any form, using alcohol in moderation, visiting an oral healthcare provider at least every six months, practicing good oral hygiene, living a healthy lifestyle, having good nutrition, and providing immunization against the human papillomavirus (HPV) for sons and daughters. Precancerous lesions (oral dysplasia) tend to be on the floor of mouth, lateral border of the tongue, etc. The raspberry gel is sticky, and we are trying to get the adherent patch dosage as a “burst delivery” every 15 minutes. Patients are told not to eat or drink for 30 minutes, and the patch is designed for use multiple times throughout the day. It will be a prescription agent. Research has been conducted in Dr. Schwendeman’s lab on oral cancer patients with polyglycolic acid and polylactic acid implants (properties similar to resorbable sutures) that can deliver drug in the former cancer site. We know our patient population, they may not apply something four times a day. Polymeric implants for cancer chemotherapy may be one of the answers.

MPG: I want to thank Dr. Mallery for her time and expertise. I also wish to thank Allison Walker for her assistance with this interview.

March, 2012|Oral Cancer News|

Video: What You Need to Know About Oral Cancer: Surgical Management of Oral Cancer

Source: http://www.youtube.com/

March, 2012|Oral Cancer News|

Erlotinib dose doubled for smokers with head/neck cancer

Source: www.oncologyreport.com
Author: Miriam E. Tucker

Giving smokers a higher, short-course dose of erlotinib before definitive surgery for squamous cell carcinoma of the head and neck resulted in favorable responses for the first patients evaluated in a small pilot study.

Investigators gave 300 mg of erlotinib (Tarceva) to smokers daily and 150 mg daily to nonsmokers who had a waiting period of more than 14 days before scheduled surgery for head and neck cancer. Seven of the 10 patients evaluated so far had partial responses and 3 had stable disease, according to a poster presented at a head and neck cancer symposium sponsored by the American Society for Radiation Oncology. The study was based on recent data in non–small cell lung cancer

(NSCLC) patients showing that smokers metabolize erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, twice as quickly as do nonsmokers (J. Clin. Oncol. 2009;27:1220-6), said lead author Dr. Mercedes Porosnicu of Wake Forest Baptist Medical Center in Winston Salem, N.C. That study established the maximum tolerated dose of erlotinib at 300 mg daily in NSCLC patients who smoke.

Dr. Poroniscu’s presentation included the case study of a smoker with a very large oral cavity tumor protruding through his lips. He was described as being in significant pain and unable to eat or chew. The first CT scan showed a tumor of at least 8 cm and there was “significant metabolic activity” on PET scan.

“At 6 days of erlotinib treatment, his tumor was obviously smaller and he could chew, eat, and talk. Metabolic activity on PET scan dropped to 44% compared to initial tumor metabolic activity,” Dr. Porosnicu said. “At the end of 14 days’ treatment, his tumor was at least 20% smaller, and he had gained 5 pounds. His surgery wasn’t delayed, and the only treatment-related toxicity was a minimal skin rash.”

A total of 12 patients have been treated to date, for an average of 18.2 days, she reported. Nine were smokers and three were nonsmokers. All patients, smokers and nonsmokers, tolerated the erlotinib dose well with no serious adverse events and no delays in the scheduled time of surgical intervention. There were no grade 3 or 4 toxicities.

Of 10 evaluable patients (including 8 smokers who received 300 mg), 7 (including 5 smokers) showed a partial response, as defined by at least a 20% reduction in maximum tumor diameter. The other three patients (all smokers) showed stable disease. Two of the 12 treated patients received shorter duration treatment but nonetheless displayed good responses.

January, 2012|Oral Cancer News|

What accounts for racial differences in head/neck cancer?

Source: www.drbicuspid.com
Author: DrBicuspid Staff

Why are African-Americans more likely than Caucasians not only to be diagnosed with head and neck cancer, but also to die from the disease? While the answer isn’t a simple one, differences in lifestyle, access to care, and tumor genetics may be partly to blame, according to a new study from Henry Ford Hospital.

The study, which was presented September 14 at the American Academy of Otolaryngology – Head and Neck Surgery Foundation’s annual meeting in San Francisco, also found that African-Americans are more likely to be past or current smokers, one of the primary risk factors for head and neck cancer.

“We’re really trying to understand why African-Americans with head and neck squamous cell carcinoma do so poorly,” said lead author Maria Worsham, PhD, director of research in the department of Otolaryngology – Head and Neck Surgery at Henry Ford, in a news release. “Using a comprehensive set of risk factors that are known to have some bearing on the disease, we’re able to gain a better understanding of what contributes to racial differences and work to help improve patient care.”

This year alone, it’s estimated that 52,140 new cases of head and neck cancer will be diagnosed, and roughly 11,460 will die in 2011 from oral cavity and pharyngeal and laryngeal cancers, she and her team members noted.

African-Americans are more likely to be diagnosed with late-stage head and neck squamous cell carcinoma (HNSCC) and have a worse five-year survival rate than Caucasians. It’s unknown whether significant biological rather than socioeconomic differences account for some of the disparities in outcomes.

To get at the root of these differences, Worsham and her team used a large Detroit multiethnic group of 673 patients with HNSCC. Most notably, 42% of the study group was African-American.

The researchers took a broad approach to the study, examining many of the intertwined variables influencing health and disease to look for differences among African-Americans and Caucasians. In all, the study focused on 136 risk factors, including demographics (age, race, gender), smoking and alcohol use, access to care, and type of cancer treatment (radiation and/or surgery). Tumor characteristics, including stage, biology, and genetics, also were examined.

Among the study findings:

  • While 88% of African-Americans in the study had medical insurance, the majority had Medicare or Medicaid instead of private health insurance.
  • African-Americans also were more likely to be unmarried or living alone, both of which previous studies suggest have a negative impact on quality of life and survival.
  • In terms of cancer treatment, African-Americans in this study were more than two times more likely than Caucasians to receive radiation therapy. The study showed fewer African-Americans (43%) opted for surgery than Caucasians (49%).
  • African-American tumors were six to seven times more likely to present with lymphocytic response.
  • Compared to Caucasian tumors, African-American tumors were almost two times more likely to have loss of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and gain of the small inducible cytokine A3 (SCYA3) gene. CDKN2A is important to cell cycle regulation, and the SCYA3 gene product has dual roles of tumor lymph node metastasis and local host defense against tumors in HNSCC.
September, 2011|Oral Cancer News|