Monthly Archives: February 2005

Israeli project develops novel solution to dry mouth

  • 2/28/2005
  • David Brinn
  • Israel21c (www.israel21c.org

Most of us may suffer dry mouth from time to time. But for 80 million people in the developed world who suffer from the condition – technically known as xerostomia – it is a permanent condition caused by a lack of lubrication in the mouth

Now an Israeli undertaking – under the project name Saliwell – has developed a removable device called the GenNarino that stimulate saliva production through electro-stimulation.

“Our devices apply a low energy level of electricity to the right nerves that lead to a higher level of saliva secretion,” explained Dr Andy Wolff, Saliwell project coordinator at Assuta Medical Centers in Israel.

Xerostomia is defined as the subjective feeling of dry mouth and is frequently associated with a reduction in salivary glands function.. It’s a chronic and mostly irreversible condition induced as a side effect by over 500 types of medication used to treat chronic diseases (like hypertension, depression, etc.), and by radiation therapy for head & neck cancer patients. Xerostomia also is a typical symptom of some auto-immune diseases (Sjögren?s syndrome is the most prominent) and other conditions.

According to Wolff, salivary glands malfunction in the mouth for a number of reasons. These include diseases such as autoimmune diseases and diabetes, treatments like chemotherapy, radiation therapy or from the side effects of medication. Those who are afflicted have the condition for life.

They endure the many unpleasant aspects of xerostomia. “It disturbs their speech, their swallowing, tasting,” explains Wolff. “It wakes them up during the night, causes increased tooth decay, and it also makes it difficult to wear dentures.” In addition, he continues, it can have negative social side effects.

Saliwell’s solution is based on applying stimulating signals on the salivary glands associated nerves, causing the salivary glands to naturally and constantly secrete saliva at an enhanced capacity. As demonstrated by the famous researcher Pavlov, secretion of saliva increases sharply as a result of a stimulus (food in his experiments).

Saliwell devices apply this principle and by mimicking natural stimulation, achieve the same effect of increased salivation, which is the most efficient means to relieve xerostomia. Natural saliva not only relieves dryness; it also contains essential dental decay-fighting factors and other components critical for oral health.

According to Wolff, Saliwell’s process turns a dry mouth into a moist one rather quickly. Dentists make an impression of the patient’s mouth and send it to the manufacturer, which in turn embeds the circuitry between two sheets of dental material and returns the device to the dentist. The patient recharges the battery through the year using a Saliwell tester and recharger, and returns the GenNarino once a year to the manufacturer to fabricate a new one or install fresh batteries.

The importance of the Saliwell solution was acknowledged by the European Commission (EC) 5th Framework Program, which approved funding for the development of the device. The Saliwell Project was launched in July 2002, coordinated by Assuta Medical Centers, Tel Aviv, Israel, and with the participation of leading European technological and medical organizations.

About 200 double blind experiments were performed in three medical centers (Charité Hospital Berlin, Hospital Clínico San Carlos Madrid and Università di Napoli Federico II). The results are showing a statistically significant increase in salivation following electrical stimulation versus placebo, where no increase in salivation was detected.

“The trials showed there was a positive effect and people were satisfied with its use.
It just needs some final adjustments. We hope to have CE approval within 6 months and FDA approval sometime after that,” Wolff told ISRAEL21c.

To reassure those who are hesitant to place something electrical in their mouths, Wolff says that there are no side affects to the electricity. The patients were also asked to fill out a questionnaire. The findings were overwhelmingly positive, with no complaints, despite it being a prosthetic that fits in the mouth. As an added bonus, said Wolff, some users claim that it alleviates the problem of dry eyes, an ailment that also commonly afflicts dry mouth sufferers.

Wolff, the mastermind behind the GenNarino, began his’love affair’ with dry mouth when he spent three years at the National Institute of Health in Washington from 1986-89 at their National Institute of Dental Research.

“I was working in the oral biology department and the general focus was on dry mouth. Since there was no good solution, I’d been thinking about it ever since,” said Wolff, who has authored 40 articles and book chapters on salivary glands and xerostomia and owns a US patent for the Saliwell solution.

Since he established Saliwell, Wolff and his team have focused on a pioneering approach: the development of electronically based, intra-oral therapeutic and diagnostic devices. With the help of the latest developments in nanotechnology, electronic miniaturization and software, Wolff said that Saliwell is creating an intra-oral ‘intelligent ambient’, opening the doors to numerous innovative applications.

Wolff, who until May 2004, served as director of the Hospital Dentistry Department at Assuta, said that previous devices used to treat dry mouth failed due to their impracticality.

“There used to be a device called the Salitron about 15 or 20 years ago meant to treat dry mouth. But it was cumbersome, a big video appliance you had to carry around with you. It wasn’t practical. On the other hand, the GenNarino is the size of a tooth,” he said.

Likewise, he added, the multitudes of medications to treat the condition each have their own limitations.

“Dry mouth can be treated by medication, but its effects are limited by time, there are many restrictions to who can take it, and there are side effects,” Wolff said.

As opposed to the available treatments, Saliwell offers a permanent, effective, comfortable and side effect free treatment for xerostomia. According to Wolff, the device will reduce the expenses which patients and the medical services spend today to treat dry mouth and their damaged dentition.

And they’re not stopping with the GenNarino. Another solution to dry mouth that Saliwell is developing is their Saliwell Crown which is attached to a regular permanent dental implant. Their Crown can be simply inserted into an implant by any dentist familiar with implants. Since the Crown is screwed in, when the battery runs out it can be easily removed and replaced. This happens roughly once a year, according to Wolff.

Clinical trials are expected to take place during the year at independent centers in Berlin, Madrid and Naples.

February, 2005|Archive|

Smokeless tobacco use among professional baseball players: survey results, 1998 to 2003

  • 2/28/2005
  • H H Severson et al.
  • Tobacco Control 2005;14:31-36

Objective:
The use of smokeless tobacco (ST) (snuff and chewing tobacco) has long been associated with baseball in the USA. This article reviews six years of survey data from major and minor league baseball players to evaluate trends in tobacco use and quitting patterns over time in order to gain insight into the effects of past interventions and to document continued intervention needs.

Method:
Surveys were distributed by athletic trainers to major and minor league professional baseball players during spring training session in the six years from 1998 to 2003. The surveys were anonymous and identified only by team, level of league, and other self reported demographic data.

Results:
ST use among professional baseball players remains much higher than among young males in the general population, and use is most prevalent among white non-Hispanic players. There was a significant decrease in ST use among minor league players from 1998 to 2003, with seven day self reported use declining from 31.7% in 1998 to 24.8% in 2003. No significant year to year changes were observed for major league players. Major league players’ self reported past week use rates, estimated at 35.9% in 1998 and at 36% in 2003, were consistently higher than those of minor league players. Self reported prevalence of past month cigarette and cigar smoking was much lower than ST use for both major and minor league players.

Conclusions:
Six years of survey data confirm a continuing high use of ST among professional baseball players. Results suggest that the effects of the broad spectrum ST control efforts launched over the past decade may have been stronger among minor than major league players. Stronger policy interventions at the major league level and multi-level efforts, including programmes to increase the use of effective quitting aids and assistance, at both levels of play are needed. Future research is needed to further clarify changes in ST practices among professional players and set policy intervention directions.

Authors:
H H Severson(1), K Klein(1), E Lichtensein(1), N Kaufman(1) and C T Orleans(2)

Authors’ Affiliations:
1 Oregon Research Institute, Eugene, Oregon, USA
2 Robert Wood Johnson Foundation, Princeton, New Jersey, USA

February, 2005|Archive|

Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review

  • 2/28/2005
  • Aimee R. Kreimer et al.
  • Cancer Epidemiology Biomarkers & Prevention Vol. 14, 467-475, February 2005

Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear.

We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site.

Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0).

Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site–specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx.

Authors:
Aimee R. Kreimer(1,2), Gary M. Clifford(1), Peter Boyle(1) and Silvia Franceschi(1)

Authors’ Affiliations:
(1) International Agency for Research on Cancer (IARC), Lyon, France and
(2) Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland

February, 2005|Archive|

Human papilloma virus in oral squamous cell carcinoma in a Mexican population

  • 2/25/2005
  • BR Ibieta et al.
  • Oral Surg Oral Med Oral Pathol Oral Radiol Endod, March 1, 2005; 99(3): 311-5

Objective:
To determine the human papilloma virus (HPV) infection in oral cancer and its association with smoking and drinking habits.

Study design:
A cross-sectional study was performed; samples were collected from 51 patients with histological diagnosis of squamous-cell carcinoma were collected at the Instituto Nacional de Cancerologa in Mexico City. HPV infection was detected by polymerase chain reaction, and the clinical characteristics of this population were analyzed.

Results:
Fifty samples out of 51 were positive for beta-globin; 21 (42%) cases were HPV-positive, and 14/21 were positive for HPV-16. We found more samples positive in men than in women (71% vs 29%). No differences were observed between HPV-positive and -negative patients in relation to smoking and drinking habits (81% vs 79%).

Conclusions:
HPV infection was present in 42% of patients with oral squamous-cell carcinoma (OSCC); HPV-16 was the most frequent type, identified in 66.6%. Other cofactors participate in the development of OSCC, independent of HPV infection.

Authors:
BR Ibieta, M Lizano, M Fras-Mendivil, JL Barrera, A Carrillo, L Ma Ruz-Godoy, and A Mohar

February, 2005|Archive|

Cancer Therapy Dropped in U.S. Is Revived in China

  • 2/25/2005
  • Andrew Pollack
  • New York Times (nytimes.com)

Chinese biotechnology companies have long copied American drugs for use in their home markets. But one Chinese imitator may now save a novel cancer treatment from oblivion after it was abandoned by its American developer.

Shanghai Sunway Biotech, a biotechnology company in Shanghai, has licensed worldwide rights to the therapy from Onyx Pharmaceuticals, based in Emeryville, Calif., people at both companies said.

It is a sign that China is plowing ahead in certain areas of medicine that are regarded more cautiously in the United States.

The therapy uses a virus that has been genetically modified to attack cancer cells but avoid normal cells. The treatment, called Onyx-015, elicited great interest among cancer researchers a few years ago when it showed the ability to shrink tumors in midstage clinical trials.

But there were challenges delivering the therapy to tumors because the immune system attacks the virus. Some scientists also considered the treatment a form of gene therapy, a technique that fell into disfavor after the death of a teenager in a gene therapy trial at the University of Pennsylvania.

Onyx stopped work on the virus treatment in 2003 to devote its money to a more conventional cancer drug that is now in late stage trials with Bayer, the German pharmaceutical company. Onyx could not find a partner willing to pay for further development of the virus therapy.

Unbeknownst to Onyx, however, Sunway researchers duplicated its approach after reading a paper published by Onyx scientists in 1996. Sunway has taken the treatment through clinical trials in China and thinks it is close to winning approval to sell it for head and neck cancer.

“They cloned our work after our paper came out,” said Frank McCormick, founder of Onyx and the main inventor of the technology. He said Onyx had known nothing about Sunway’s activities all these years.

Onyx’s technology was not protected by patents in China because the company had not applied for them. But Sunway now says it wants to develop and sell the treatment in countries where Onyx does have patents, including the United States.

So Sunway has licensed the rights, according to Dr. McCormick and to Hu Fang, the president of Sunway. Dr. Hu said his company was paying $1 million up front, and might pay up to $10 million more if the drug won approval in the United States and Europe, plus royalties on sales. A spokeswoman for Onyx confirmed that an agreement had been reached but would not provide financial details.

“They weren’t fazed by the negative publicity around gene therapy in the U.S.,” said Dr. McCormick, who is now director of the cancer center at the University of California, San Francisco. “They just had a different attitude.”

The first and only approval of a gene therapy by any regulatory agency in the world happened in China in 2003.

That therapy, developed by SiBiono GeneTech, based in Shenzhen, uses a virus to deliver to tumors a gene called p53 that helps kill cancerous cells. SiBiono’s approach is very similar to one being tested in late stage clinical trials by Introgen, a company in Austin, Tex.

Even if the Onyx therapy wins approval in China, Sunway will need to conduct clinical trials in the United States to get approval in this country and to conform to tougher American manufacturing standards.

Dr. Hu said his company had made some improvements to the Onyx therapy to make it more effective. Dr. McCormick agreed, and said he was happy his work had been imitated. “I was a bit shocked at first,” he said. “But since we haven’t been able to find anyone in the U.S. to support the project, it’s better than having it die on the vine. Over all, I’m actually delighted.”

He said he expected to go to China soon to celebrate the first approval anywhere of the therapy he invented.

February, 2005|Archive|

Cigarette ads target women

  • 2/24/2005
  • Bowling Green, OH
  • Laura Collins
  • Bowling Green State University News (BGNews.com)

University graduate student Michelle Grindstaff presented “Women, Smoking and Advertising: Have We Come a Long Way, Baby?” yesterday to students and faculty members in Hanna Hall.

The presentation, a part of the Women’s Center’s Brown Bag Lunch series, discussed strategies tobacco companies use in their advertisements to entice female consumers.

The pressure to be thin and womens want for gender equality are two of the issues that cigarette advertisements focus on when selling their product to women, Grindstaff said.

The media also plays a large role in creating so-called beauty and gender norms that unrealistically portray women’s bodies in society, she said. For example, the average model is 5-foot-11-inch and 117 pounds, while the average woman is 5-foot-4-inch and 140 pounds. Tobacco companies use the fact that many women are looking for ways to lose weight, by healthy and unhealthy means, as a marketing tool, she said.

“Smoking is one example of the destructive behaviors encouraged in the media to achieve unrealistic standards of beauty for women,” she said.

The other common theme that appears in cigarette ads is that smoking promotes gender equality. It sends that message that if you smoke, you’ll be one of the guys, Grindstaff said.

She also discussed ads that target women by using the phrase “find your voice.” Since it has often been a metaphor for speaking out, it looks like it promotes gender equality, she said.

“You can get throat cancer from smoking. You’re not going to find your voice, you’re going to lose it,” Grindstaff said.

She closed her presentation by presenting different ads from magazines that show the themes discussed. Understanding what the ads are doing is one way to combat it.

“It is important to resist media representations of women’s bodies and challenge advertising that utilizes false notions of gender equality to sell products,” she said.

Amy Schueter, a student at the University, said that the presentation served as starting place for many people who want to talk to others about advertising myths and the dangers of smoking.

“Knowing this information, it will be easier to talk to others about not smoking,” Schueter said. “Also, it’s more meaningful coming from someone you know rather than a commercial or something.”

February, 2005|Archive|

Cancer study seeks clues to minorities’ high morbidity rates

  • 2/24/2005
  • Angela Stewart
  • The Star Ledger (www.nj.com/news/ledger)

A newly awarded $1.2 million federal grant will help researchers unlock the mysteries behind why minorities in New Jersey suffer worse cancer outcomes than whites, with interventions developed to alleviate those causes, officials announced yesterday at a Jersey City news conference.

The three-year grant, awarded by the National Institutes of Health, will establish a Center for Excellence in Health Disparities, to be led by the University of Medicine and Dentistry of New Jersey in Newark. The university will collaborate with two other institutions — the Cancer Institute of New Jersey in New Brunswick and New Jersey City University in Jersey City– on7 the project that will, among other things, seek to find the underlying causes of cancer disparities.

“New Jersey is the most racially and ethnically diverse state in the nation and is consistently ranked among the top 10 states in the nation with the highest cancer morbidity and mortality among minority populations,” said Rep. Robert Menendez (D-13th Dist. ), who helped secure the funding, along with Sen. Jon Corzine (D-N.J.) and Rep. Steven Rothman (D-9th Dist.).

African-American men in New Jersey are more than twice as likely as white men to die from prostate cancer, said Diane Brown, who heads UMDNJ’s Institute for the Elimination of Health Disparities, founded in 2001. The new program, initially targeting its outreach in Newark and Jersey City, will build upon the efforts already underway at UMDNJ, where a cancer center is set to open on the Newark campus in the summer of 2006.

African-Americans won’t be the only targeted group. Latinos also have a higher incidence of certain types of cancers, including those affecting the stomach, cervix, liver and gall bladder, Brown noted.

“As the center develops, other New Jersey communities will be included,” she said.

In addition to helping increase the number of minorities screened for cancer, the project also will work to enroll more minorities in trials where new cancer therapies are being tested. Ronald Morton Jr., director of urologic oncology at the Cancer Institute, said researchers are likely to find disparities arising from a number of things, including environmental causes and problems with access to health care.

“It’s not like some of the other problems where you can say it’s this one gene,” he said.

Rhonda Jones, 50, of Irvington, is an African-American cancer-survivor who had never even heard of throat or tongue cancer until she was diagnosed with both a little more than a year ago.

“You know your body and you know when something is wrong,” said Jones, who said weight loss and losing her voice were symptoms of her disease.

Jones ended up undergoing cancer surgery, followed by chemotherapy and radiation, an experience she described as “very scary.” Today, Jones, a one-time American Cancer Society outreach worker, readily shares her experience because she finds that many minorities are still afraid to admit they have the disease.

“They think it’s taboo, like a curse or something. It’s okay to share your information so you can help somebody else,” she said.

February, 2005|Archive|

Submandibular Gland Transfer for Prevention of Xerostomia After Radiation Therapy

  • 2/24/2005
  • Jana Rieger et al.
  • Arch Otolaryngol Head Neck Surg. 2005;131:140-145

Objective:
To assess swallowing outcomes in patients with oropharyngeal carcinoma in relation to the Seikaly-Jha procedure for submandibular gland transfer (SJP). The SJP has recently been described as beneficial in the prevention of xerostomia induced by radiation therapy in patients with head and neck cancer.

Design:
Inception cohort.

Setting:
University-affiliated primary care center.

Patients:
A phase 2 clinical trial was conducted from February 1, 1999, through February 28, 2002, to evaluate SJP in patients with head and neck cancer. During that period, a consecutive sample of 51 patients who underwent surgical resection and reconstruction with a radial forearm free flap for oropharyngeal carcinoma were referred for functional assessment of swallowing after completion of adjuvant radiation therapy. At 6 months after surgery, swallowing assessments for 24 patients were available.

Intervention:
The cohort of 24 patients included 13 who had preservation of 1 submandibular gland (SJP group) and 11 who did not (control group).

Main Outcome Measures:
Quantitative and qualitative aspects of swallowing were obtained to determine whether patients in the SJP group performed more optimally than those in the control group.

Results:
Baseline and stimulated salivary flow rates were significantly different between groups. Patients in the SJP group were able to move the bolus through the oral cavity and into the pharynx faster than those in the control group. In addition, patients in the SJP group swallowed less often per bolus than patients in the control group. The complete swallowing sequence was twice as long in controls.

Conclusions:
The SJP for submandibular gland transfer appears to be beneficial in promoting more time-efficient swallowing behaviors. This efficiency has implications for the overall well-being and nutritional status of patients with head and neck cancer.

Authors:
Jana Rieger, PhD; Hadi Seikaly, MD; Naresh Jha, MBBS; Jeffrey Harris, MD; David Williams, MD; Richard Liu, MD; Tim McGaw, DDS; John Wolfaardt, PhD

Author Affiliations:
Craniofacial Osseointegration and Maxillofacial Prosthetic Rehabilitation Unit, Caritas Health Group (Drs Rieger, Seikaly, and Wolfaardt), Faculty of Rehabilitation Medicine (Dr Rieger), Division of Otolaryngology Head and Neck Surgery (Drs Seikaly, Harris, and Liu), Division of General Surgery (Dr Williams), and Department of Dentistry (Drs McGaw and Wolfaardt), University of Alberta; Division of Surgical Oncology (Dr Seikaly) and Department of Radiation Oncology (Dr Jha), Cross Cancer Institute, Edmonton, Alberta.

February, 2005|Archive|

New devices for people who suffer dry mouth or lack of saliva

  • 2/23/2005
  • News-Medical.net

For dry mouth sufferers Saliwell’s innovative patented devices brings welcome relief by restoring natural saliva production through electro-stimulation.

Most of us may suffer dry mouth from time to time. But for 80 million people in the developed world it is a permanent condition caused by a lack of lubrication in the mouth. With IST programme funding Saliwell has developed devices that stimulate saliva production. “Our devices apply a low energy level of electricity to the right nerves that lead to a higher level of saliva secretion,” says Dr Andy Wolff, Saliwell project coordinator at Assuta Medical Centers in Israel.

Their removable device, GenNarino, is custom made which sufferers wear whenever they need it. Dentists make an impression of the patient’s mouth and send it to the manufacturer, which in turn embeds the circuitry between two sheets of dental material and returns the device to the dentist. The patient recharges the battery through the year using the Saliwell tester and recharger, and returns the GenNarino once a year to the manufacturer to fabricate a new one or install fresh batteries, offering a kind of permanent service.

There are no side affects to the electricity and they are now conducting double blind placebo controlled clinical trials. After about 200 experiments they have found a significant increase in saliva secretion and relief to the patients.

Alongside the clinical trials there have been questionnaires. The findings are positive with no complaints, despite it being a prosthetic that fits in the mouth, says Wolff. As an added bonus, users claim that it alleviates the problem of dry eyes, an ailment that also commonly afflicts dry mouth sufferers.

Wolff hopes they can market the GenNarino next year once it gets the CE mark. They first want to commercialise it themselves and then merge with a larger company which, for example, supplies medical devices.

Another solution is their Saliwell Crown which is attached to a regular permanent dental implant. Their Crown can be simply inserted into an implant by any dentist familiar with implants. Since the Crown is screwed in, when the battery runs out it can be easily removed and replaced. This happens roughly once a year, according to Wolff.

After getting ethics committee permission trials on the Crown are about to begin in three different independent centres in Berlin, Madrid and Naples.

Both the GenNarino and the Saliwell Crown have been patented.

As for the causes of dry mouth, salivary glands malfunction in the mouth for a number of reasons. These include diseases such as autoimmune diseases and diabetes, treatments like chemotherapy, radiation therapy or from the side effects of medicine. Once afflicted it remains for the rest of the life.

As a result as Wolff explains: “It disturbs their speech, their swallowing, tasting, it wakes them up during the night, causes increased tooth decay, and it also makes it difficult to wear dentures.” Wolff says current solutions are less than adequate relying mainly on expensive drugs that cause adverse side affects.

In addition, continues Wolff, it can have negative social side effects. With dry mouth it is harder to communicate so people become reclusive. Difficulties in sleeping means they also become tired and lacklustre.

In the UK 1000 elderly people were interviewed about their expectations for such a device. In this survey 15.5% have dry mouth. In looking for a solution, “they expect a non-chemical solution that could permanently solve their problem without having to resort to drugs,” says Wolff. “We hope we have fulfilled their expectations,” concludes Wolff.

February, 2005|Archive|

Is There Still a Role for Induction Chemotherapy for Head and Neck Cancer?

  • 2/18/2005
  • Houston, TX
  • Adam S. Garden
  • Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1059-1060

Nasopharynx cancer is a disease known for chemosensitivity compared with its counterparts in the head and neck, and is also notorious for a greater incidence of systemic spread compared with squamous cancers arising from other head and neck sites. Thus, the appeal of systemic therapies to treat this disease is great. In the current issue of the Journal of Clinical Oncology, Chua et al1 report a form of meta-analysis evaluating cisplatin-based induction therapy for nasopharynx cancer. By pooling the data from the two largest trials exploring the role of induction chemotherapy, it was hoped that the combination of two independently negative trials would gain sufficient statistical power to result in a positive result. Alas, with respect to overall survival, the overall trial results remain negative.

The current analysis adds to the growing database of neoadjuvant chemotherapy trials in head and neck cancer that have not demonstrated a survival advantage for the use of induction therapy. These results are consistent with the Meta-Analysis of Chemotherapy in Head and Neck Cancer Collaborative Group’s finding, which revealed no significant survival benefit associated with the use of neoadjuvant chemotherapy.2

In the 1990s, induction chemotherapy was a critical component in the management of patients when organ preservation was the goal. Often, survival equivalence was a satisfactory end point. The Veterans Affairs and European Organization for Research and Treatment of Cancer larynx preservation studies demonstrated that not all patients with advanced larynx and hypopharynx cancers required surgery.3,4 However, both studies made a priori assumptions that induction therapy was required. Similar to other studies of concurrent chemoradiotherapy, the results of the Radiation Therapy Oncology Group and Head and Neck Intergroup Larynx Preservation Trial 91-11 demonstrated that a concurrent chemotherapy approach was superior to radiation alone in achieving larynx preservation.5 More importantly, it demonstrated that the concurrent approach achieved an improvement in larynx preservation compared with induction chemotherapy. Finally, patients receiving induction therapy did not have a significantly better larynx preservation rate than those receiving radiation alone, but they did have more treatment-related toxicity.

The results of the study by Chua et al1 leave us with the same questions we had at the initiation of the trials on which the analysis was based. It unfortunately reinforces the conclusion that induction therapy demonstrates some effect of neoadjuvant therapy on the disease, but ultimately not on the patient. We are left questioning whether the neoadjuvant approach is conceptually valid, when yet to be proven in the appropriate circumstances. Proponents argue that neoadjuvant therapy has failed to demonstrate efficacy for several reasons: inadequate study design, inadequate drug intensity, inadequate drug efficacy, or inadequacy of the local therapies allowing for the systemic component to demonstrate its effect. To address these issues, several groups have investigated taxane-based induction therapy6 or have advocated the combination of an induction regimen with concurrent chemoradiotherapy.7

Despite demonstrating a lack of efficacy (with an evidence-based approach) with respect to survival or organ preservation to date, induction therapy remains a component of many practices, and my editorial comments would be disingenuous if I did not admit that we still treat some of our patients with induction therapy, and continue to develop protocols that try to define a role for this therapy. One reason is the perception that neoadjuvant therapy remains an effective strategy for managing systemic micrometastases. For patients with low T stage (but high N stage) tumors, particularly if the disease is in the low neck, the probability of systemic failure can be greater than the local regional failure; the latter can be successfully managed with local therapies. Thus, a systemic treatment seems reasonable, though proof of efficacy is lacking.8 A second practical reason is that neoadjuvant therapy can be initiated quickly in the occasional patient with either very advanced disease (or rapidly progressive disease) who find themselves in a clinical setting in which radiation therapy can not be started expeditiously. Finally, induction therapy for some represents a predictive marker, as the clinician can choose the “appropriate” local therapy based on response to induction therapy.

To improve outcomes in head and neck cancer, a multidisciplinary approach is a key element. However, the integration of these approaches remains a challenge. The strongest evidence to date establishes concurrent chemoradiotherapy as the most effective approach in controlling advanced disease.2 This has been demonstrated for head and neck cancer in general, as well as for specific subsites, such as nasopharynx, oropharynx, and larynx. This has also been demonstrated in the nonsurgical and postoperative settings. The vast majority of studies have used radiation alone as the control, and improvements with a concurrent approach have been made by decreasing the rates of primary and nodal recurrence. These advances, however, have come at the cost of increased toxicity.

We are entering an era of “targeted” therapies for head and neck cancer, in which relatively nontoxic therapies can effect unique molecular changes in the cancer cell, leading to improvement in tumor control. One lesson early experiences are teaching us is that there are multiple targets, and one molecularly targeted therapy may be a success only in a subgroup of our patients. Betensky et al9 demonstrated that molecular heterogeneity may confer different risks to patients that, if unaccounted for, could result in an unsuccessful trial due to underpowering of the trial design. The same can be said for our experiences with neoadjuvant therapy in that it is a valid concept, but the appropriate population needs to be identified. Perhaps it is time to stop testing the approach for all patients with advanced disease, but rather design trials to identify which subgroups will truly benefit.

It is also an opportunity to think of radiation as another agent, rather than a competing therapy, thus developing optimal multiagent therapies for the appropriate scenarios. Each agent has its differing mechanisms of causing cell death, and each, a set of toxicities. Striking the appropriate balance with all therapies and taking advantage of their tumoricidal effects, while minimizing their acute and late sequelae, remains the ultimate challenge.

Author’s Affiliation:
The University of Texas M. D. Anderson Cancer Center, Houston, TX

REFERENCES
(1)Chua D, Ma J, Sham J, et al: Long-term survival after cisplatin-based chemotherapy and radiotherapy for nasopharyngeal carcinoma: A pooled data analysis of two phase III trials. J Clin Oncol 23:1118-1124, 2005

(2)Pignon J, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group—Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949-955, 2000

(3)The Department of Veteran Affairs Larynx Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 19921

(4)Lefebvre J, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. J Natl Cancer Inst 88:890-899, 1996

(5)Forastiere A, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003

(6)Shin D, Glisson B, Khuri F, et al: Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck. Cancer 95:322-330,

(6)Kies M, Haraf D, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16:2715-2721, 1998

(7)Johnson F, Garden A, Palmer J, et al: A phase II study of docetaxel and carboplatin as neoadjuvant therapy for nasopharyngeal carcinoma with early T status and advanced N status. Cancer 100:991-998, 2004

(8)Betensky R, Louis D, Cairncross J: Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol

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