Monthly Archives: November 2006

The promise of viral therapies

  • 11/30/2006
  • Toronto, Ontario, Canada
  • Carolyn Abraham
  • GlobeandMail.com

At any other moment in Brad Thompson’s life it might have sounded too strange. But when University of Calgary researchers approached the entrepreneur in 1998 about the potential of using a common stomach bug to fight cancer, their timing was uncanny.

Dr. Thompson had lost his mother to lung cancer that year, his uncle to esophageal cancer and he himself had been diagnosed with melanoma.

“I was open to thinking about cancer, and thinking about it in a new way,” said the microbiologist, who was working with a biotech firm on bowel diseases at the time.

“I’m awfully glad they came to see me.”

Eight years later, Dr. Thompson, now CEO of Calgary-based Oncolytics Biotech, is in the vanguard of one of the more promising, if unconventional, approaches to treating cancer patients: deliberately infecting them with viruses.

Cancer cells, it so happens, are particularly vulnerable to viral invasion and the century-old concept has cured laboratory mice, pushed some end-stage cancer patients into long-term remission and raised hopes for a new generation of cancer therapies.

Hundreds of patients in clinical trials in Canada, the United States and Europe have volunteered to catch a cold, a stomach bug, a mutant form of herpes and even a chicken flu.

Researchers have found cancer cells lack the defences that healthy cells have to protect themselves from infection. Flipped into overdrive, a cancer cell never shuts down the pathway that allows a viral intruder to waltz in, replicate and wreak havoc.

Several viruses have now passed Phase 1 human safety tests with encouraging results and larger Phase 2 trials to test their efficacy are in the works.

But getting a new medicine to market is never easy and those involved say that transforming a virus into a viable drug presents more obstacles than usual. For one, it can be tricky to control a dose when the drug has the power to replicate itself.

“This is a much more complicated kind of drug, if you can even call it a drug,” said David Stojdl, a scientist working at the Ottawa Regional Cancer Centre in the field.

As well, despite years of university research, the field still labours to alter its fringe image. Some academic scientists are struggling to attract the interest of drug companies with pockets deep enough to continue development. Not everyone has been as receptive as Dr. Thompson to the idea of using one disease to fight another.

“Industry is much more conservative, and for them this can be too much,” said John Bell, an Ottawa scientist and long-time pioneer in the field.

But the need for private-sector investment is critical, he said: “You can treat mice with government funding, not people.”

Earlier this year, China became the first country to approve a viral therapy, giving the nod to a modified version of the common cold to treat cancers of the head and neck. Yet the cold bug now being sold by a Shanghai biotech firm is a copycat of a virus first developed by a U.S. company, which despite encouraging results from mid-stage clinical trials, dropped it in favour of a more conventional drug.

Yet most experts feel it’s time to look beyond convention.

“As an industry, we haven’t been very successful in new approaches to treating to cancer,” Dr. Thompson said. “Most of the advances have been the result of better diagnosis . . . survival times have improved with earlier detection.”

He, for example, credits his own quick melanoma diagnosis to his beloved dog, Mozart, who sniffed so steadily at the malignant mole on his leg that he rushed to the doctor to have it checked.

Dr. Thompson knows from experience that “the therapies we use to treat cancer are still the same ones we’ve had for years.

“Viral therapies are promising, they’re safe, they target the cancer cells and there’s not much collateral damage.”

It began as one of those weird medical observations. An Italian doctor in the early 1900s noticed that after he gave a prostitute a rabies vaccine to treat a dog bite — a shot that contains viral material — her cervical cancer regressed.

The mysterious connection — bolstered by anecdotes about cancer patients getting better when they battled a cold, flu or other infection — led to a few experiments. Reports from the 1940s suggested that measles might somehow help to quell lymphoma. In the 1950s, doctors in the Soviet Union literally fed poliovirus to cancer patients.

But not until the early 1990s did virologist Patrick Lee and colleagues at the University of Calgary piece the puzzle together.

They showed that in a cancer cell, a pathway crucial for growth and survival is stuck in the “on” position. Like a porch light that never shuts off, this defective mechanism that makes a cell malignant also allows a virus to find the door easily.

Once inside that cell, the viral intruder makes so many copies of itself they bust the host from the inside out and set off to find another.

Dr. Lee had centred his work on the reovirus, a bug so common it usually triggers at least one bout of diarrhea in most people by the age of 3, but it helped to spread wide interest in the viral field.

Researchers at McMaster University in Hamilton and others in Britain, for example, have homed in on the anti-cancer powers of herpes. Researchers at Duke University in North Carolina are running with a crippled poliovirus, and at Minnesota’s Mayo Clinic it’s a modified form of measles. University of Ottawa scientists, meanwhile, have been studying a range of microbes with an eye to tailoring them to be a tumor’s worst enemy.

On a recent blustery morning at the Ottawa Regional Cancer Centre, Dr. Bell and his team crammed into his cluttered office to discuss the learning curve.

Dr. Bell, an affable, silver-haired man in black jeans, is a senior scientist with Cancer Care Ontario and a co-founder of the Canadian Oncolytic Virus Consortium, which is establishing standards in the field.

It was, for example, once thought that a virus might simply be injected into a tumour. But since cancer usually kills when it spreads, Dr. Bell said, it’s clear viruses have to be given intravenously to flush the system, “if they are going to be useful.”

Research suggests that 80 per cent of cancer cells have a defect that makes them susceptible to a virus. But “just as viruses have evolved ways to enter our cells,” he said, “our immune system has evolved to stop them.”

Figuring out how to keep the body’s immune system from killing viruses that have been dispatched to kill the cancer is one of the field’s key issues.

“It’s been a matter of finding that balance between attenuating a virus to minimize side effects and yet not to the point where it’s losing its anti-cancer punch.”

Most safety trials have not even reached a maximum-tolerated viral dose in patients, he suspects, because they have involved either less virulent strains, or those genetically tweaked to be less toxic.

Dr. Bell’s initial investigations focused on the Newcastle virus, a flu bug that strikes chickens. Since few patients are likely to have been exposed to the fairly obscure virus, he estimates it has “a two-week window to attack tumour cells before [a patient’s] immune system gears up to destroy it.”

A few years ago, Dr. Bell teamed up with a Maryland company called Provirus Inc., to run clinical trials of Newcastle virus. Thirty patients with a range of advanced cancers were enrolled in Ottawa and another 18 in Hamilton in 2001.

McMaster professor Sébastien Hotte, a medical oncologist at the Juravinski Cancer Centre, said the Phase 1 testing and follow-up was designed only to determine safe doses of the virus, but it also showed promising results in six of the 18 patients, who had all exhausted standard treatments.

Dr. Hotte, author of the report that is soon to be published, said the virus was delivered by IV twice a week for three weeks. If the treatment was well tolerated, the infusions continued over several months.

The first dose prompted “flu-like” symptoms, but they disappeared with subsequent doses as the body acclimatized to the treatment.

“We were quite happy,” Dr. Hotte said, “some patients had signs of disease regression.”

The most dramatic example involved a woman in her 40s with end-stage cervical cancer who received the viral infusions for nine months. Some months after treatment ended, surgeons operating to remove a benign growth on her bladder discovered her cancer had disappeared. More than three years later, Dr. Hotte said, the woman is still alive.

He said the therapy is “not ready for prime time,” but noted that larger trials of the virus in patients with cervical and colorectal cancers are to begin in Hamilton next year.

“Given that we have a lot of people who are drug averse, [patients] find this approach very attractive. It’s not a chemical, it’s not chemotherapy, and that,” he said, “is appealing to them.”

It was Calgary virologist Dr. Lee, along with his postdoctoral student Jim Strong and his graduate student Matt Coffey, who first paid Dr. Thompson a visit in 1998.

Since then, the garden-variety reovirus that led to their breakthrough has become the cornerstone of Oncolytics.

So far, 100 patients have received treatment with Reolysin in six preliminary safety trials, three of them in Alberta. The company has also been testing it on cancer patients in England and recently received approval to expand the trials.

“About half the patients have no side effects at all,” Dr. Thompson said. “The most common side effects in the other half are mild fever . . . mild joint or muscle pain . . . and a bit of tiredness.”

As well, a few patients in the trials who were not expected to live long are still alive, he said.

The U.S. National Cancer Institute is so intrigued by the company’s strategy that earlier this year it announced it will pay for a multicentre clinical trial to test Oncolytics’ stomach bug on patients with melanoma and ovarian cancer. “That’s a big endorsement,” Dr. Thompson said.

Dr. Bell is no longer involved with the Maryland company developing the Newcastle virus. With the Ottawa teams’ hopes of genetically tweaking viruses to increase their ability to selectively target tumour cells, there was a parting of ways.

Said David Stojdl, who was once a postdoctoral student in Dr. Bell’s lab: “We can engineer them to do whatever we want.” Currently, he is working out ways to specifically arm viruses to break into tumour cells only, but still “trip the alarm” that will bring immune guards to protect healthy cells.

It’s also possible, Dr. Bell said, that they could design a virus primed to attack cancer stem cells, which have recently been revealed as the engines driving several types of tumours.

But in the meantime, he sees a major challenge to the field: finding and keeping private-sector investment. Grants from government agencies such as Cancer Care Ontario help, he said. But academic grants are barely a sliver of what is needed to run clinical trials.

The Ottawa group has most recently been exploring a partnership with a California company to focus on vaccinia, a cowpox relation best known as an ingredient in the smallpox vaccine.

Dr. Bell understands that using live viruses as a medical treatment naturally raises concerns. In 1999, for example, Jesse Gelsinger, an 18-year-old American who suffered from a rare metabolic disorder, died after doctors injected him with a weakened cold virus as a means of delivering a corrective gene to his ailing liver.

“People are fearful, perhaps,” Dr. Stojdl agreed, “that you don’t have control of its distribution throughout the body.”

Harold Atkins, a medical oncologist who has worked with Dr. Bell for eight years, also noted that the virus field doesn’t follow the traditional course of other therapies.

“With chemical drugs,” Dr. Atkins said, “there’s 40 to 50 years of understanding how drugs interact with the body and find their target, and with this, it’s not clear those lessons apply.”

Still, the Ottawa group is forging ahead. In a tower that overlooks the cancer centre, a small, stark white biofactory of negative air-pressure rooms is under construction where the researchers hope to produce their cancer-fighting viruses for clinical trials.

“Our purpose here,” Dr. Bell said, “is to get it far enough along so that it’s not viewed as a fringe concept.”

From the vantage point of a private-sector player, Dr. Thompson is more optimistic. The drug industry may have been initially reluctant, he agreed, because of safety concerns. But safety trials have gone well.

“[Pharmaceutical companies] have never really lost interest. They’ve always been watching over our shoulders.”

Industry’s main concerns, he said, are, “Can you produce enough and will it work well?”

Viruses like the common cold and stomach bug may be ubiquitous in nature, but producing enough of them for use in treatment is a challenge.

Dr. Thompson explained that 10 trillion viral particles are needed for one IV treatment, and a patient may receive as many as 45 treatments over a nine-month period.

After a six-year investigation, Oncolytics has turned to a European manufacturer to grow Reolysin in human cell lines, where the virus can replicate itself and then be harvested.

Dr. Thompson suspects the interest from big companies will follow from the next phase of trials, which he said is preferable as an initial investor: “You are rewarded for the risk you undertake.”

November, 2006|Archive|

Focusing Radiation In The Affected Area Leads To Better Control Of Cranial-Base Tumor

  • 11/30/2006
  • Boston, MA
  • Pascal Pommier et al.
  • MedicalNewsToday.com

Proton beam radiation therapy, a very precise type of radiation treatment, may be an effective treatment for advanced adenoid cystic carcinoma that has spread to the cranial base, according to a study from the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (MGH). In the November issue of Archives of Otolaryngology – Head and Neck Surgery, the research team describes results from 11 years of using proton therapy to treat this tumor, which can be dangerous when it spreads into the complex structures at the base of the skull.

“We are very encouraged by our results, in which local tumor control of advanced adenoid cystic carcinoma of the cranial base compared very favorably with results reported from traditional radiation therapy,” says Annie Chan, MD, MGH Radiation Oncology, who led the study.

Frequently originating in the salivary glands, adenoid cystic carcinoma is an indolent but aggressive tumor that is usually treated surgically if diagnosed at an early stage. However, when it originates in or spreads into the cranial base – a complex area involving the cranial nerves, the eyes and critical brain structures – it is impossible to remove the tumor safely. Traditional radiation therapy has had limited success in controlling the tumors’ growth, largely because the sensitive adjacent structures sharply limit the ability to deliver a strong enough dose.

Proton therapy takes advantage of an inherent quality of the positively charged atomic particles. As they travel through tissues, protons release most of their energy in a concentrated burst near the end of their range, which allows the power of the proton beam to be focused extremely precisely and spares surrounding structures. The MGH has used proton therapy to treat a variety of benign and malignant conditions since 1961 and in 2001 opened the Burr Proton Therapy Center, at the time the second hospital-based center in the world. Currently, proton therapy is offered in 25 centers worldwide, five of which are in the U.S.

The current study reports on a group of patients with very locally advanced adenoid cystic carcinoma involving the cranial base who were treated with high-dose proton beam therapy during the years 1991 through 2002. The majority of the patients could not undergo surgery, as the tumors were very advanced and involved critical structures in the brain or the cranial base. Patients were treated with high-dose proton beam radiation therapy, with treatment plans individually designed to target their specific tumors.

With proton beam treatment, only 9 percent of patients had local recurrence of their tumors, while with traditional radiation tumors recur locally more than 70 percent of the time. With tumors controlled locally in most patients, cancer that did recur was in the form of distant metastasis. However, more than half the patients remained free of recurrence through the end of the study period, up to eight years after surgery. Although blindness is a common side effect of traditional radiation to this area, none of the patients developed blindness with the proton beam treatment.

While the results of this study – the first known report of the use of proton beam therapy to treat this tumor – are better than trials of other types of radiation treatment, the researchers note that conducting the kind of randomized trial required to confirm a treatment’s superiority would be difficult for such a rare tumor. However, multi-institutional prospective studies could further study the use of proton beam therapy to treat this rare and aggressive malignancy.

“We are now investigating whether combining proton beam radiation therapy with chemotherapy could further improve the outcome for these patients,” says Chan, an assistant professor of Radiation Oncology at Harvard Medical School. The study was supported by the National Institutes of Health.

Authors & affiliations:
Pascal Pommier, MD, formerly of MGH Radiation Oncology and now at the Anticancer Center in Lyon, France; Jay Loeffler, MD, Nobert Liebsch, MD, PhD, Fred Barker II, MD, Judy Adams, CMD, and Vrishali Lopes of the MGH; Daniel Deschler, MD, and Derrick Lin, MD, Massachusetts Eye and Ear Infirmary; James McIntyre, MD, now at North Shore Medical Center; and Mark Varvares, MD, now at St. Louis University School of Medicine.

November, 2006|Archive|

Australia to Subsidize Merck Cervical Cancer Vaccine

  • 11/29/2006
  • Canberra, Australia
  • Vesna Poljak and Gemma Daley
  • Bloomberg.com

Australia’s government agreed to add Merck & Co.’s Gardasil vaccine to its subsidized health program, reversing an earlier decision to exclude the shots which protect against viruses causing 70 percent of cervical cancer.

Prime Minister John Howard said Australia will spend A$436 million ($342 million) making the vaccine free for women aged 12 to 26. The turnabout followed an agreement by its distributor CSL Ltd. to cut the price by 27 percent, and criticism from the Australian university where it was developed.

“Gardasil will be available for a nationwide vaccination campaign commencing next year,” Howard told reporters in Canberra today. “This remarkable Australian drug can be made cheaply available to women.”

Cervical cancer kills about 250,000 women annually, making it the second-biggest cause of death among female cancer patients globally, according to the World Health Organization. It is caused predominantly by human papillomavirus, or HPV, a virus carried by about 440 million people.

Shots protecting against the sexually transmitted virus should be mandatory for preteen girls and available worldwide, researchers from Johns Hopkins University in Baltimore wrote in the scientific journal Nature Reviews Cancer in September.

Gardasil is the first vaccine aimed at preventing cervical cancer. It is “an immense innovation,” Didier Hoch, president of Sanofi Pasteur MSD, the vaccine joint venture between Merck & Co. and Sanofi-Aventis SA, said this week.

European Union-member states should lead other governments by making the vaccinations mandatory for all girls aged 11-12 years, the U.K.’s Lancet medical journal said last month.

In the U.S., insurance carriers for about 94 percent of privately insured Americans will pay for the vaccines, Whitehouse Station, New Jersey-based Merck said this month.

Australian of the Year

Immunologists Ian Frazer and Jian Zhou made a discovery at the University of Queensland more than 15 years ago that led to the development of Gardasil and rival Cervarix, made by GlaxoSmithKline Plc. Frazer was named 2006 Australian of the Year, the nation’s top honor, for his work.

“The government’s decision, combined with an ongoing cervical cancer-screening program, will be a significant step towards further reduction of cervical cancer risk for Australian women,” Frazer said in a separate statement today.

Health First

A government advisory committee on Nov. 8 rejected a request by Melbourne-based CSL to subsidize Gardasil, citing the expense of the three-shot course. The rejection, supported by Health Minister Tony Abbott, was challenged a day later by the Prime Minister Howard. A full course costs about A$460.

University of Queensland Vice-Chancellor John Hay said this month that it should never have been necessary for the Prime Minister to intervene.

“The Government has put the health of Australian women ahead of the Budget bottom line,” Mukesh Haikerwal, president of the Australian Medical Association, said in a separate statement today.

State and federal governments in Australia spend more than A$90 million annually screening for cervical cancer using a procedure known as a Pap smear.

The program has cut deaths from cervical cancer by about 60 percent since 1985 and has halved the number of cases of cervical cancer, the Department of Health and Ageing said in a statement yesterday. Australia has the second-lowest incidence of cervical cancer and the lowest mortality rate from cervical cancer in the world.

Boys Too

Gardasil was approved June 16 by the department’s Therapeutic Goods Administration for females aged 9 to 26 years and males aged 9 to 15.

After a two-year catch up period inoculating women as old as 26 years with Gardasil, the National Immunisation Program aims to target schoolgirls aged 12 and 13 to immunize them before they become sexually active.

HPV viruses are responsible for about 20 percent of head and neck cancers, and are a chief cause of cancer of the penis, anus and some types of skin cancer in men who have sex with other men. HPV viruses, of which there are about 200 different types, also cause genital warts.

Silent Carriers

In 98 percent of infections, the body’s own immune response successfully fights the virus. In the remainder of cases, it will persist, potentially causing disease, the University of Queensland’s Frazer said.

“From a public health point of view, vaccinating men and women is the quickest way to reduce the total burden of virus in the community,” Frazer said in an interview in Melbourne last month. The vaccine is safe in men though more studies are needed to demonstrate its efficacy, he said.

Infected men who are immunized will secrete protective antibodies along with the virus, making them less likely to spread HPV, Frazer said.

“Since this is a virus that you generally don’t know you’ve got, especially in men, there’s a case to be made for immunizing men to prevent them from infecting women even if they’ve already been infected themselves,” he said.

November, 2006|Archive|

Chemoprevention of Head and Neck Cancer With Aspirin

  • 11/28/2006
  • Buffalo, NY
  • Vijayvel Jayaprakash, MBBS et al.
  • Arch Otolaryngol Head Neck Surg. 2006;132:1231-1236

Objective:
To evaluate the chemopreventive potential of aspirin against head and neck cancer.

Design:
Hospital-based case-control study.

Setting:
National Cancer Institute–designated comprehensive cancer center.

Patients:
Individuals who received medical services at the Roswell Park Cancer Institute, Buffalo, NY, between 1982 and 1998 and who completed a comprehensive epidemiologic questionnaire.

Main Outcome Measure:
Aspirin use among 529 patients with head and neck cancer and 529 hospital-based control subjects matched by age, sex, and smoking status.

Results:
Aspirin use was associated with a 25% reduction in the risk of head and neck cancer (adjusted odds ratio, 0.75; 95% confidence interval, 0.58-0.96). Consistent risk reductions were also noted in association with frequent and prolonged aspirin use. Further, a consistently decreasing trend in risk was noted with increasing duration of aspirin use (Ptrend = .005). Risk reduction was observed across all 5 primary tumor sites, with cancers of the oral cavity and oropharynx exhibiting greater risk reduction. When analyzed by smoking and alcohol exposure levels, participants moderately exposed to either showed a statistically significant 33% risk reduction (adjusted odds ratio, 0.67; 95% confidence interval, 0.50-0.91), whereas participants exposed to both heavy smoking and alcohol use did not benefit from the protective effect of aspirin. The reduction in risk was relatively more significant in women.

Conclusions:
Aspirin use is associated with reduced risk of head and neck cancer. This effect is more pronounced in individuals with low to moderate exposure to cigarette smoke or alcohol consumption.

Authors:
Vijayvel Jayaprakash, MBBS; Nestor R. Rigual, MD; Kirsten B. Moysich, PhD; Thom R. Loree, MD; Maureen A. Sullivan Nasca, DDS; Ravi J. Menezes, MSc; Mary E. Reid, PhD

Authors’ affiliations:
Departments of Epidemiology, Division of Cancer Prevention and Population Sciences (Drs Jayaprakash, Moysich, and Reid and Mr Menezes), Head and Neck/Plastic Surgery (Drs Rigual and Loree), and Dentistry and Maxillofacial Prosthetics (Dr Sullivan Nasca), Roswell Park Cancer Institute, Buffalo, NY

November, 2006|Archive|

Stem Cells May Lead to Cancer Vaccine

  • 11/26/2006
  • Louisville, KY
  • Miranda Hitti
  • WebMD.com

Tests on Mice Suggest Vaccine for Lung Cancer Might Be Possible, but Long Way Off

It might be possible to make a cancer vaccine using embryonic stem cells, University of Louisville scientists report. Their prediction is based on early lab tests on mice. No such vaccine exists for humans yet.

But results from mouse tests suggest the “exciting possibility” that embryonic stem cell vaccines might prevent cancer, write researcher John Eaton, PhD, and colleagues.

Their findings were presented yesterday in Prague, Czech Republic, at a joint symposium of the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI), and the American Association for Cancer Research (AACR).

“At present, all I can say is that so far it looks good, and that, unless something unexpected happens, this strategy might someday be applied to humans at high risk for development of cancer,” Eaton says in an EORTC news release.

Eaton is a professor of medicine and pharmacology/toxicology and the Brown Chair of Cancer Biology at the University of Louisville’s medical school.

Eaton’s team used embryonic stem cells taken from mouse embryos to make two experimental vaccines against mouse lung cancerlung cancer.

One of the vaccines contained only embryonic stem cells. The other vaccine contained embryonic stem cells plus a growth factor to boost immune response.

The scientists split the test mice into three groups. One group of mice got the vaccine containing only stem cells. A second group got the vaccine containing both the stem cells and the growth factor. The third group got neither vaccine.

The mice were then exposed to chemicals that cause lung cancer.

All of the unvaccinated mice developed the disease.

But only 40% of the mice that got the stem cell vaccine and 10% of those that got the vaccine with both stem cells and growth factor developed lung tumors during the 27-week study.

No drop was seen in the number of adult bone marrow stem cells in the mice, according to the report.

November, 2006|Archive|

Low dose vitamin A derivative does not prevent head and neck tumors

  • 11/24/2006
  • Italy
  • staff
  • Xagena Medicine (www.xagena.it)

Taking a vitamin A derivative called Isotretinoin (Accutane/Roaccutane) did not reduce the risk of second primary tumors or improve survival in patients with stage I or II head and neck squamous cell cancers (HNSCC). In addition, current smokers had an increased risk of second primary cancers and death.

HNSCCs are the fifth most common cancers and sixth leading cause of cancer related death today. In 2002, there were 600,000 new cases diagnosed worldwide.

Some studies have suggested that vitamin A derivatives called retinoids may halt or even reverse growth of head and neck tumors.
A clinical trial of high doses of a retinoid called isotretinoin, widely used to treat cystic acne, in patients with HNSCC found that those receiving isotretinoin developed fewer second primary tumors, particularly smoking-related tumors. However, there were substantial side effects among those who received the high-dose isotretinoin, and subsequent studies of the compound have shown mixed results.

To assess the effect of lower, more tolerable doses of isotretinoin on the development of second primary tumors and survival among patients with early-stage HNSCC, Fadlo R. Khuri, of the Emory University School of Medicine in Atlanta, and colleagues conducted a randomized clinical trial of 1190 patients diagnosed with stage I or II HNSCC. Patients were randomly assigned to receive low-dose Isotretinoin (30 mg/day) or a placebo for 3 years.

Researchers continued to monitor the patients for 4 or more years after treatment. This clinical trial is the largest chemoprevention study to date to examine the use of retinoids in patients with early-stage HNSCC.

The study found that low-dose isotretinoin did not reduce the rate of second primary tumors or improve overall survival compared with a placebo. Current smokers in both the treatment and placebo groups had an increased rate of second primary tumors and death.

The authors conclude that the study provides substantial evidence that doctors should work with patients on smoking cessation, and they do not recommend isotretinoin monotherapy as a preventive agent for second primary tumors in people with stage I or II HNSCC.

“After two decades of research that has drastically changed the principles and practice of cancer chemoprevention, the present chapter on translational cancer chemoprevention with retinoid monotherapy in HNSCC closes with this definitive report,” the authors write. “A tolerable dose of Isotretinoin was ineffective in preventing the development of second primary tumors in this phase III trial, further reinforcing results from two other negative phase III retinoid trials in lung and aerodigestive cancer chemoprevention.”

In an accompanying editorial, Sarah J. Freemantle, of Dartmouth Medical School, and colleagues discuss the role of retinoids in chemoprevention, calling Khuri’s findings “definitive” and consistent with past findings in similar trials. The authors suggest that further evaluation of other classical and nonclassical retinoids and of combination regimens should continue. They write, “It is now important to uncover the basis for this paradoxical lack of isotretinoin clinical chemoprevention activity.”

Source: Journal of the National Cancer Institute, 2006

November, 2006|Archive|

Fluorescence Visualization Detection of Field Alterations in Tumor Margins of Oral Cancer Patients

  • 11/24/2006
  • Vancouver, British Columbia, Canada
  • Catherine F. Poh et al.
  • Clinical Cancer Research Vol. 12, 6716-6722, November 15, 2006

Purpose:
Genetically altered cells could become widespread across the epithelium of patients with oral cancer, often in clinically and histologically normal tissue, and contribute to recurrent disease. Molecular approaches have begun to yield information on cancer/risk fields; tissue optics could further extend our understanding of alteration to phenotype as a result of molecular change.

Experimental Design:
We used a simple hand-held device in the operating room to directly visualize subclinical field changes around oral cancers, documenting alteration to fluorescence. A total of 122 oral mucosa biopsies were obtained from 20 surgical specimens with each biopsy being assessed for location, fluorescence visualization (FV) status, histology, and loss of heterozygosity (LOH; 10 markers on three regions: 3p14, 9p21, and 17p13).

Results:
All tumors showed FV loss (FVL). For 19 of the 20 tumors, the loss extended in at least one direction beyond the clinically visible tumor, with the extension varying from 4 to 25 mm. Thirty-two of 36 FVL biopsies showed histologic change (including 7 squamous cell carcinoma/carcinomas in situ, 10 severe dysplasias, and 15 mild/moderate dysplasias) compared with 1 of the 66 FV retained (FVR) biopsies. Molecular analysis on margins with low-grade or no dysplasia showed a significant association of LOH in FVL biopsies, with LOH at 3p and/or 9p (previously associated with local tumor recurrence) present in 12 of 19 FVL biopsies compared with 3 of 13 FVR biopsies (P = 0.04).

Conclusions:
These data have, for the first time, shown that direct FV can identify subclinical high-risk fields with cancerous and precancerous changes in the operating room setting.

Authors:
Catherine F. Poh1,2,3, Lewei Zhang1, Don W. Anderson5, J. Scott Durham5, P. Michele Williams1,3, Robert W. Priddy1, Ken W. Berean6, Samson Ng1, Olivia L. Tseng7, Calum MacAulay4 and Miriam P. Rosin2,7

Authors’ affiliations:
1 Faculty of Dentistry, University of British Columbia, Departments of 2 Cancer Control Research, 3 Oral Oncology, and 4 Cancer Imaging, British Columbia Cancer Agency, Departments of 5 Surgery (Otolaryngology) and 6 Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada, and 7 School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada

OCF Note:
The device mentioned in the above article is being sold in the US as the Velscope.

November, 2006|Archive|

Cyclooxygenase-2 Inhibition Suppresses {alpha}v{beta}6 Integrin-Dependent Oral Squamous Carcinoma Invasion

  • 11/22/2006
  • United Kingdom
  • Staff
  • Cancer Res., November 15, 2006; 66(22): 10833-42

Worldwide oral squamous cell carcinoma (OSCC) represents about 5.5% of all malignancies, with approximately 30,000 new cases each year in the United States. The integrin alpha(v)beta(6) and the enzyme cyclooxygenase-2 (COX-2) are implicated in OSCC progression and have been suggested as possible therapeutic targets.

Each protein also is reported to identify dysplasias at high risk of malignant transformation, and current clinical trials are testing the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) at preventing OSCC development. Given the probable increased expression of alpha(v)beta(6) and COX-2 in OSCC and the inhibition of several integrins by NSAIDs, we investigated whether NSAIDs affected alpha(v)beta(6)-dependent cell functions.

We found that expression of both alpha(v)beta(6) and COX-2 was significantly higher in OSCC compared with oral epithelial dysplasias. Neither protein preferentially identified those dysplastic lesions that became malignant. Using OSCC cell lines, modified to express varying levels of alpha(v)beta(6), we assessed the effect of COX-2 inhibition on cell invasion. We found that the COX-2 inhibitor NS398 inhibited specifically alpha(v)beta(6)-dependent, but not alpha(v)beta(6)-independent, OSCC invasion in vitro and in vivo, and this effect was modulated through prostaglandin E(2) (PGE(2))-dependent activation of Rac-1.

Transient expression of constitutively active Rac-1, or addition of the COX-2 metabolite PGE(2), prevented the anti-invasive effect of NS398. Conversely, RNA interference down-regulation of Rac-1 inhibited alpha(v)beta(6)-dependent invasion.

These findings suggest that COX-2 and alpha(v)beta(6) interact in promoting OSCC invasion. This is a novel mechanism that, given the ubiquity of alpha(v)beta(6) expression by head and neck cancers, raises the possibility that NSAIDs could protect against OSCC invasion.

Source:
Tumour Biology Laboaraotry, Cancer Research UK Clinical Centre,
Queen Mary’s University, Charterhouse Square

November, 2006|Archive|

BC Cancer Agency study sheds new light on controlling oral cancer

  • 11/22/2006
  • Vancouver, Canada
  • BC Cancer Agency

Vancouver, B.C. – A study recently published in Clinical Cancer Research
takes BC Cancer Agency researchers into the operating room to shed new light
on oral cancer. Using a hand-held blue light device that could chance
clinical practices, pioneered at the BC Cancer Agency, researchers examined
oral cancer patients for pre-cancerous and cancerous lesions that are not
visible to the naked eye. The light device makes cancerous lesions that look
like normal tissue under regular white light appear as dark patches.

“This light device could revolutionize surgical practice, allowing us to see
previously hidden changes at the edge of cancers during surgery,” says Dr.
Scott Durham, surgeon, Vancouver General Hospital.

The light device detected dark patches that extended beyond the tumour and
its surgical boundary in 19 of the 20 patients involved in the study.
Biopsies taken from the tissue outside the surgical boundary confirmed the
existence of both cancerous and abnormal cells.

Recognizing the tissue surrounding oral cancers is at high-risk for
developing cancer, surgeons generally remove an arbitrary width of 10
millimeter or more of normal-looking tissue surrounding the tumour, if
anatomically possible. However, the study has shown that this approach still fails to completely remove the high-risk tissues in many patients.

“By using the light device, we were able to see that cancerous and
pre-cancerous lesions are not evenly distributed around the tumour,” says
Dr. Catherine Poh, Oral Pathology Specialist at the BC Cancer Agency and
Principal Investigator of the study. “Current surgical practices sometimes
do not eliminate oral cancers completely and this contributes to a high rate
of recurrence.”

Oral cancer is a deadly disease with little change in the survival rate in
more than three decades. The results of the study could potentially affect
the management of the 3,100 new cases of oral cancer developing in Canada
each year.

“There is a pressing need to develop new approaches that can be used
clinically in order to improve the outcome for oral cancer patients,” says
Dr. Miriam Rosin, Director of the BC Cancer Agency’s Oral Caner Prevention
Program. “The results of the study are certainly promising.” Dr. Rosin adds that the study is an important step forward in integrating optical technology and the management of this disease.

“It’s exciting to see this new technology developed in British Columbia
finally making it into the surgical theatre,” says BC Cancer Agency
scientist Dr. Calum MacAulay.

The study, a part of the BC Cancer Agency’s Oral Cancer Prevention Program,
is the effort of a multidisciplinary research team that includes oral
medicine and pathology specialists, dentists, ENT surgeons, physicists and
engineers. The study was undertaken collaboratively by the BC Cancer Agency, University
of British Columbia, Simon Fraser University, and Vancouver General
Hospital. The National Institute of Dental Craniofacial Research provided funding to
pioneer the light source.

The BC Cancer Agency, an Agency of the Provincial Health Services Authority,
is committed to reducing the incidence of cancer, reducing the mortality
from cancer, and improving the quality of life of those living with cancer.
It provides a comprehensive cancer control program for the people of British
Columbia by working with community partners to deliver a range of oncology
services, including prevention, early detection, diagnosis and treatment,
research, education, supportive care, rehabilitation and palliative care.
The BC Cancer Foundation raises funds to support research and enhancements
to patient care at the BC Cancer Agency.

OCF Note: The light source that is being referred to in this article is currently being sold as the Velscope in Canada and the USA by LED Dental.

November, 2006|Archive|

High HPV Concentrations, Cigarette Smoking Significantly Raise Risks of Later Cervical Cancer

  • 11/21/2006
  • Philadelphia, PA
  • staff
  • PharmaLive (www.medadnews.com)

Cigarette smoking and concurrent infection with high levels of the virus associated with cervical cancer can increase cancer risk by as much as 27 times, according to a study published in the November 2006 issue of Cancer Epidemiology, Biomarkers & Prevention.

Anthony Gunnell, a medical biostatistician and epidemiologist and colleagues at the Karolinska Institutet in Stockholm reviewed the medical exams of women with non-invasive cervical cancer in situ (the most common type) and cancer-free women in one of the largest studies to date to examine the relationships between smoking and the human papilloma virus (HPV). The virus and smoking behavior have long been associated with the disease, but not enough evidence has come forth to determine how either may cause the disease.

Gunnell’s study, in fact, suggests that both may create a biochemical synergy that propels the disease. The researchers looked at “Pap” smear examination data from 105,760 Swedish women and identified 499 women with cervical cancer in situ, along with 499 cancer-free women as controls. For these women, they compared their smoking behavior with concentrations (known as viral load) of HPV-16, the viral strain most associated with cervical cancer. The researchers found that a combination of high viral loads and smoking during the time they were initially examined resulted in very high risk of later cervical cancer.

“We were surprised to see this dramatically increased risk among women with high viral loads who smoked,” Gunnell said.

Among their findings:

– Women who smoked and had a high HPV-16 load during their first exam had a 27-fold increased risk of later cancer than women who smoked but did not have an HPV infection.

– Women who were positive for HPV-16 (irrespective of amount of viral load) and were smokers had a 14-fold increased risk over women who were HPV-16 negative and smoked.

– Nonsmoking women with high HPV-16 loads had just a 6-fold risk compared to HPV-negative nonsmokers.

“Our initial analyses centered on whether smoking was an independent risk factor for cervical cancer,” said Gunnell. “Clearly, both exposures need to be present at the same time for there to be interaction.

“Our study would imply a synergistic action between HPV and smoking that would greatly increase the likelihood of women developing cervical cancer if they are HPV-positive smokers. This would put them in a risk group worthy of careful monitoring.”

The study, which also may partly explain why some women may not get cervical cancer despite smoking behavior or being HPV-positive, had too few women with high viral loads for the researchers to declare both smoking and HPV, by themselves, caused the disease. But since it was one of the largest studies to examine this relationship, it strongly suggests directions that future research should take to explore a causative effect.

The researchers also found a relationship between smoking duration and cancer. “We found a statistically significant multiplicative interaction between the duration of smoking and HPV presence causing cervical cancer,” Gunnell said. “One explanation for this interaction could involve the influence of smoking on persistence of HPV infection, probably due to localized immune suppression. Conversely, it could be related to the progression of neoplastic growth, since HPV and smoking appear to alter the levels of certain cytokines, which are involved in controlling abnormal cell growth. More likely, the combination of both mechanisms are contributory factors.

In any event, confirmation of an interaction between cigarette smoking and HPV in cervical cancer development is of vital importance to public health, considering the widespread exposure to the virus and cigarette smoking in young women at risk for the disease, he said.

Cervical cancer is one of the leading causes of cancer deaths worldwide, and death rates are particularly high in developing countries. Although rates of incidence and mortality have dropped by 50 percent in the past 20 years, out of the 9,700 women diagnosed just in the United States this year, 3,700 will die. Early diagnosis and treatments have helped curb mortality rates, but the disease still remains one of the world’s deadliest. In addition, it remains more common among Hispanic and African-American women.

Gunnell’s colleagues in the study included Trung Tran, Anna Torrang, Paul Dickman, Par Sparen and Nathalie Ylitalo, of the Karolinska Institutet. Juni Palmgren also is a faculty member at Stockholm University. Their work was supported by grants from the U.S. National Institutes of Health, the Swedish Cancer Society and the Danish National Research Foundation.

November, 2006|Archive|