Monthly Archives: May 2008

Acupuncture reduces pain and dysfunction in head and neck cancer patients after neck dissection

  • 5/31/2008
  • New York, NY
  • staff
  • 7th Space Interactive (7thspace.com)

New data from a randomized, controlled trial found that acupuncture provided significant reductions in pain, dysfunction, and dry mouth in head and neck cancer patients after neck dissection. The study was led by David Pfister, MD, Chief of the Head and Neck Medical Oncology Service, and Barrie Cassileth, PhD, Chief of the Integrative Medicine Service, at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Pfister presented the findings today at the annual meeting of the American Society for Clinical Oncology.

Neck dissection is a common procedure for treatment of head and neck cancer. There are different types of neck dissection, which vary based on which structures are removed and the anticipated side effects. One type – the radical neck dissection – involves complete removal of lymph nodes from one side of the neck, the muscle that helps turn the head, a major vein, and a nerve that is critical to full range of motion for the arm and shoulder.

“Chronic pain and shoulder mobility problems are common after such surgery, adversely affecting quality of life as well as employability for certain occupations,” said Dr. Pfister. Nerve-sparing and other modified radical techniques that preserve certain structures without compromising disease control reduce the incidence of these problems but do not eliminate them entirely. Dr. Pfister adds, “Unfortunately, available conventional methods of treatment for pain and dysfunction following neck surgery often have limited benefits, leaving much room for improvement.”

Seventy patients participated in the study and were randomized to receive either acupuncture or usual care, which includes recommendations of physical therapy exercises and the use of anti-inflammatory drugs. For all of the patients, at least three months had elapsed since their surgery and radiation treatments. The treatment group received four sessions of acupuncture over the course of approximately four weeks. Both groups were evaluated using the Constant-Murley scale, a composite measure of pain, function, and activities of daily living.

Pain and mobility improved in 39 percent of the patients receiving acupuncture, compared to a 7 percent improvement in the group that received usual care. An added benefit of acupuncture was significant reduction of reported xerostomia, or extreme dry mouth. This distressing problem, common among cancer patients following radiotherapy in the head and neck, is addressed with only limited success by mainstream means.

“Like any other treatment, acupuncture does not work for everyone, but it can be extraordinarily helpful for many,” said Dr. Cassileth. “It does not treat illness, but acupuncture can control a number of distressing symptoms, such as shortness of breath, anxiety and depression, chronic fatigue, pain, neuropathy, and osteoarthritis.”

“Cancer patients should use acupuncturists who are certified by the national agency, NCCAOM [National Certification Commission for Acupuncture and Oriental Medicine], and who are trained, or at least experienced, in working with the special symptoms and problems caused by cancer and cancer treatment,” she added.

Acupuncture, a component of Traditional Chinese Medicine, originated more than 2,000 years ago. Treatment involves stimulation of one or more predetermined points on the body with needles, heat, pressure, or electricity for therapeutic effect. A report published by the Centers for Disease Control (CDC) indicated that more than 8 million Americans use acupuncture to treat different ailments. Acupuncture is being used in the palliative care of cancer to alleviate pain and chronic fatigue and to reduce postoperative chemotherapy-induced nausea and vomiting.

Note:
1. The study was funded in part from a grant by the National Cancer Institute. In addition to Drs. Pfister and Cassileth, other MSKCC contributors to the study include: Dr. Andrew Vickers, Dr. Gary Deng, Dr. Jennifer Lee, Mr. Donald Garrity, Dr. Nancy Lee, Dr. Dennis Kraus, Dr. Ashok Shaha, and Dr. Jatin Shah.

2. Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to www.mskcc.org.

May, 2008|Archive|

GenVec Announces Results Of Phase I Clinical Trial Of Head, Neck Cancer Treatment

  • 5/31/2008
  • Williamsville, NY
  • staff
  • RTT News (www.rttnews.com)

Saturday, GenVec, Inc. announced the results of a Phase I clinical trial of TNFerade in patients with head and neck cancer, reporting 9 out of 10 evaluable patients in the trial achieved an objective response to treatment.

The company also said that 4 out of the 9 patients achieved complete clinical response by response evaluation criteria in solid tumors or RECIST criteria.

May, 2008|Archive|

UCSF Stem Cell and Cancer Symposium

  • 5/30/2008
  • San Francisco, CA
  • Jeffrey Norris
  • UCSFToday (pubaffairs.ucsf.edu/today)

A new chapter in the saga of the war on cancer is being written. The subject is cancer stem cells. If more patients are to survive, then these cells must die. But many targeted treatments might be missing them.

Communication between cancer experts and stem cell experts is at an exciting, pioneering stage. An important moment in the evolution of this convergence happened last Thursday and Friday at the UCSF Mission Bay campus – a “Stem Cells and Cancer” symposium presented by the UCSF Helen Diller Family Comprehensive Cancer Center, in association with the UCSF Institute for Regeneration Medicine. The symposium brought together research leaders from around the world.

Clearly, cancers sometimes grow back even after treatment appears to have eliminated any trace of disease. But only in recent years has a critical mass of researchers begun to explore the roles of cells within cancers that appear to be stem cells, or that act like stem cells.

Forever Young, and Sometimes Deadly

Stem cells are eternally youthful, immature cells that have infinite capacity to spin off new cells. In this way, they maintain and repair tissue. In contrast, their progeny cells normally mature and grow old. The progeny assume specialized tasks, and they have little or no capability to regenerate themselves. The persistence of abnormal cancer stem cells may be the key to why many cancers come back and resist further treatment.

Most experts believe these cancer stem cells represent a very small fraction of the tumor mass. Nonetheless, a few cancer stem cells are able to re-create an entirely new tumor. By contrast, in many cases, the cancer cells that make up the bulk of the tumor are not capable of sustaining tumor growth.

It is becoming clear that treatment which targets the bulk of the tumor cells may miss some or all of these cancer stem cells. The cancer stem cells are then able to reseed the tumor. This regrowth of the cancer might not become apparent for months or years.

Researchers are already exploring treatments that specifically target cancer cells in the tissue where they are best understood – the cells of the immune system – but the first human trials have not yet begun.

Cancer stem cells share many properties with normal stem cells. Normal stem cells give rise to tissues during embryonic development, and maintain and repair tissues throughout a lifetime. It is important to study both normal and cancer stem cells, and their similarities and differences. Symposium speakers presented research on both.

The molecular fingerprints of cancer stem cells have not been precisely identified. As it stands, a tumor that can regenerate when transplanted into a mouse is regarded as a cancer stem cell. Researchers are busy sorting and describing these cells.

One of the symposium’s organizers, UCSF cancer stem cell researcher Emmanuelle Passegué, PhD, suggests that one of the earliest applications in the clinic of cancer stem cell research is likely to be the development of tests that reveal cancer stem cell prevalence, location and spread within cancer patients. Such data can provide prognostic information that can be used to weigh treatment options.

The Same Cancer Gene Acts Differently in Different Cell Types

Normal genes that go bad, called oncogenes, were shown by UCSF researchers in the 1970s to be the trigger that helps turn normal cells into cancerous cells. But in the development of cancer, the type of cell in which an oncogene becomes activated also matters.

“The consequences of the activation of a cancer gene are different in stem cells than in mature cells,” Passegué explains. Nobody fully understands these differences very well yet – but they are the focus of very active research.

Passegué’s own area of expertise is the study of cancer stem cells in leukemia, a field that really got going about a decade ago. Only in the past few years, she says, have researchers begun to identify cancer stem cells in other, solid tumors – such as colon cancer, head and neck cancer, prostate cancer, brain cancer, and the deadly skin cancer called melanoma.

“In terms of developing something that kills the cancer stem cells, eradicating the disease and leaving normal stem cells untouched, there is still plenty of work to do,” Passegué says. The first treatments are likely to be developed for leukemias, she adds.

The symposium was sponsored in part by a UC Discovery Grant. Corporate sponsors provided additional support. Symposium planners were UCSF cancer experts Martin McMahan, PhD, and Gabrielle Bergers, PhD, along with Passegué.

May, 2008|Archive|

ADVEXIN Improves Survival in Recurrent, Refractory Head and Neck Cancer Patients

  • 5/30/2008
  • Austin, TX
  • press release
  • Introgen Therapeutics Inc. (www.introgen.com)

Highlights:
– First Phase III Gene Therapy Cancer Trial in the US to Successfully Meet Study Objectives

– Primary and Secondary Efficacy Endpoints Successfully Met, Study Objective Achieved

– p53 Predictive Biomarkers Demonstrate ADVEXIN and Methotrexate Efficacy in Different and Complementary Patients

– Clinical Utility of ADVEXIN in Comparison to Methotrexate Demonstrated

Introgen Therapeutics, Inc. today announced that ADVEXIN® (p53 tumor suppressor therapy) significantly increased survival in end-stage head and neck cancer patients with prospectively identified p53 favorable profiles (7.2 vs. 2.7 months; p<0.0001). In the intent-to-treat (ITT) population, including patients with p53 favorable and unfavorable p53 profiles, ADVEXIN and methotrexate had similar overall survival while ADVEXIN had a superior safety profile. ADVEXIN is designed to restore p53 tumor suppression blocked in the majority of tumors. The compound works differently than other cancer therapies by restoring the effectiveness of p53 proteins to trigger natural tumor suppression mechanisms in cancer, without harming normal cells.

“The increase in survival and tumor response, among the p53 favorable profile patients, highlights the value of developing ‘targeted’ therapy for patients with recurrent, refractory head and neck cancer,” said Jack A. Roth, MD, inventor of ADVEXIN and Professor and Bud Johnson Clinical Distinguished Chair, Department of Thoracic & Cardiovascular Surgery, Section Chief, Thoracic Molecular Oncology, and Director, W.M. Keck Cancer Center for Innovative Cancer Therapies, M.D. Anderson Cancer Center, Houston, TX. “ADVEXIN is an outstanding example of ‘targeted’ therapy” directed at a specific molecular abnormality in cancer cells. These results underscore the effectiveness of personalized therapy by using p53 favorability profiles to select treatment. Simple tests can guide a doctor’s treatment decisions in selecting the most appropriate therapy while potentially avoiding unnecessary and highly toxic drugs.”

Currently, no gene therapy agents have been approved by the FDA. We believe ADVEXIN is the most clinically advanced gene therapy in clinical development in the U.S. Study results will be presented as a late-breaking, oral presentation this week at the American Society for Gene Therapy (ASGT) annual meeting in Boston, Mass. To access the ASGT presentation on Introgen’s web site please visit the Events page at www.introgen.com, the presentation will be posted on Thursday, May 29th.

“End-stage head and neck cancer is a particularly aggressive and deadly disease, with very few effective treatments,” said John Nemunaitis, MD, a principal investigator of the study and medical director, Mary Crowley Medical Research Center at Baylor-Charles A. Sammons Cancer Center in Dallas, TX. “In this trial, ADVEXIN more than doubled survival of patients with favorable p53 profiles compared to unfavorable p53 profile patients. ADVEXIN also demonstrated superior safety compared to methotrexate. If approved, this product would provide significant medical benefit to these seriously ill patients who have failed other treatments.”

Data presented at ASGT (Oral Presentation. Industrial Liaison: Late Stage Industry Sponsored Clinical Trials; titled: “A Phase 3, Multi-center, Open-label, Randomized Study of Adenoviral p53 Gene Therapy (ADVEXIN®) Versus Methotrexate in Patients with Recurrent, Refractory Squamous Cell Carcinoma of the Head and Neck (SCCHN) investigated the clinical benefit of ADVEXIN vs. methotrexate to address an unmet medical need. The topline results presented at the ASGT conference and described in this news release will be part of more complete submission packages, which have not yet been submitted to the FDA or EMEA. These and other data will be the basis for regulatory submissions in the United States and in Europe. The company expects to submit complete regulatory dossiers to both the FDA and EMEA by the end of the June 2008.

Study Design
This phase III, open-label, multicenter, randomized, comparative trial enrolled 123 patients with recurrent squamous cell carcinoma of the head and neck whose cancers were refractory to platinum or taxane chemotherapy. Patients were randomized to receive ADVEXIN or methotrexate as monotherapy. Recurrent, refractory (end-stage) head and neck cancer is aggressive with a poor prognosis, making it unethical to treat patients with placebo as an additional comparator.

The primary efficacy endpoint was survival with superior safety and the secondary efficacy endpoint was tumor response with superior safety. All endpoints and populations were prospectively designated, before unblinding the database, and officially amended with the FDA in 2007 prior to starting the phase III analysis. Study results compared the patients as a whole for the entire ITT population and for patients based upon favorable or unfavorable p53 biomarker profiles. Biomarkers for p53 have been shown to be excellent predictors of efficacy following ADVEXIN therapy and define a different group of patients who may benefit from methotrexate. The prospectively identified p53 biomarker profiles in the phase III study confirmed results obtained from earlier hypothesis generating analyses of biomarker profiles data from previously reported phase II study data.

Biomarker analyses were conducted with pre-treatment samples on a completely blinded basis by an independent laboratory unaware of the clinical results. Approximately half of the study patients had pre-treatment tissue samples available for testing, which yielded statistically significant findings. Using statistical analysis, the clinical characteristics of the ITT and biomarker populations demonstrated that the samples are representative of the entire treatment population. Simple, readily available, immunohistochemisty (IHC) and gene sequencing tests are performed to determine p53 profiles. Patients’ p53 profiles are determined by analyzing protein expression levels and p53 mutational status. The simple tests are available in most clinics and hospitals to detect p53 abnormalities associated with the majority of all solid tumors.

ADVEXIN Significantly Improves Survival, Tumor Responses in p53 Favorable Profile Patients

The survival analysis of the biomarker population (n=67) demonstrates that ADVEXIN and methotrexate are effective in different groups of patients, depending upon their tumors’ p53 profile, indicating ADVEXIN’s clinical utility compared to methotrexate. ADVEXIN significantly increased survival in patients with p53 favorable biomarker profiles compared to patients with p53 unfavorable profiles (7.2 months vs. 2.7 months; p<0.0001). In contrast, methotrexate patients with p53 profiles favorable for Advexin treatment had a median survival of only 4.3 months. Methotrexate improved survival in a different group of patients with the complementary p53 biomarker profiles unfavorable for Advexin efficacy (median survival 5.9 vs. 2.7 months; p = 0.0112).

Favorable p53 biomarkers were also associated with a statistically significant increase in tumor responses to ADVEXIN. Tumor response was prospectively defined as complete response, partial response or stable disease. Similar to survival, ADVEXIN and methotrexate trigger tumor responses in different patient populations defined by p53 biomarkers. Among ADVEXIN-treated patients in the pivotal phase II and III trials (T201, T301), tumor response was 78.4 percent in patients with p53 favorable profiles compared to 26.8 percent of patients with p53 unfavorable profiles (p = 0.014). In contrast, the reverse associations were seen in methotrexate-treated patients and a higher proportion of responders were observed in patients with p53 unfavorable profiles (83.3 percent) compared to patients with p53 favorable profiles (52.4 percent).

ADVEXIN Effective Among ITT Population
As expected from the p53 biomarker profiles data indicating efficacy in different patients, there was no statistical difference in survival between ADVEXIN and methotrexate in the ITT population which included both p53 favorable and unfavorable patients in both study arms (median survival 4.4 vs. 6.1 months; p = 0.236).

The tumor response outcome based upon the ITT and p53 biomarker analyses met the study’s secondary efficacy endpoint, further demonstrating ADVEXIN’s medical benefit compared to methotrexate. For the ITT population receiving ADVEXIN, there was a statistically significant increase in survival for patients with tumor responses compared to non-responders (median survival for responders 7.6 months vs. non-responders 2.9 months, p = 0.0002). Consistent with the biomarker survival results, responses to ADVEXIN and methotrexate treatment occurred in different and complementary groups of patients. The association between tumor growth control response and increased survival was not statistically significant in the methotrexate ITT population (7.5 vs. 3.8 months; p=0.156).

ADVEXIN Has Exceptional Side-Effect Profile
In this phase III study, ADVEXIN has a superior safety profile compared to methotrexate. Methotrexate side effects can be life-threatening and more dangerous than the self-limiting side effects from ADVEXIN (fever, chills, and injection site discomfort or pain.). Common side effects from the study in methotrexate patients versus ADVEXIN patients, respectively:
– Lymphopenia (abnormally low levels of lymphocytes): 25.6 percent vs. 4.9 percent

– Stomatitis (inflammation of the mouth lining): 12.7 percent vs. 0 percent

– Leukopenia (decrease in white blood cells): 12.1 percent vs. 0 percent

– Neutropenia (abnormally low level of neutrophils): 12.1 percent vs. 3.1 percent

– Pneumonia: 10.9 percent vs. 1.6 percent

A patient death associated with methotrexate was reported, while no patient deaths were associated with ADVEXIN.

The overall safety data of ADVEXIN from more than 600 patients treated demonstrate that ADVEXIN is well tolerated with localized or self-limiting events (fever, chills, and injection site discomfort) seen most often. Typically, these side effects were effectively treated with over the counter medication (ie. acetaminophen).

About Biomarkers
Biomarkers are tests or measurements that predict response to treatment or increased survival following therapy. Introgen’s molecular biomarkers include the identification of aberrant p53 function by standard assays performed by independent pathology laboratories worldwide that evaluate the sequence of p53 genes and abnormally elevated levels of p53 protein in tumor tissues. Introgen believes that application of p53 biomarkers can predict the patients who are most likely to benefit from ADVEXIN treatment. Similarly the biomarkers may also be used to predict which patients may benefit from other therapies and to identify patients that could be spared the side effects from toxic treatments unlikely to benefit the patient.

About ADVEXIN
ADVEXIN p53 therapy is a targeted molecular therapy with broad applicability in a wide range of tumor types and clinical settings because it targets one of the most fundamental and common molecular defects, abnormal p53 tumor suppressor function, associated with cancer initiation, progression and treatment resistance. ADVEXIN has demonstrated increased survival and tumor growth control in recurrent head and neck cancer patients. ADVEXIN has demonstrated clinical activity in a number of solid tumor types in multiple phase I, II and III clinical trials conducted worldwide. ADVEXIN is a registered trademark describing p53 therapy, developed by Introgen under exclusive worldwide licenses from The University of Texas M.D. Anderson Cancer Center.

Introgen Therapeutics, Inc. holds a licensing agreement with M. D. Anderson Cancer Center to commercialize products based on licensed technologies, and has the option to license future technologies under sponsored research agreements. The University of Texas System owns stock in Introgen. M. D. Anderson manages these arrangements in accordance with its conflict of interest policies.
Dr. Roth is a co-founder of Introgen, remains a shareholder and paid consultant to the company.

About Introgen
Introgen Therapeutics, Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted molecular therapies for the treatment of cancer and other diseases. Introgen is developing molecular therapeutics, immunotherapies, vaccines and nano-particle tumor suppressor therapies to treat a wide range of cancers using tumor suppressors, cytokines and genes. Introgen maintains integrated research, development, manufacturing, clinical and regulatory departments and operates multiple manufacturing facilities including a commercial scale cGMP manufacturing facility.

Note: For more information on Introgen Therapeutics, or for a menu of archived press releases, please visit Introgen’s Website at: www.introgen.com.

Contacts:
Marian Cutler
BMC Communications
(973) 517-0519
Email marian@bmccommunications.com

Channing Burke
Introgen Therapeutics, Inc.
(512) 965-0907
Email c.burke@introgen.com

May, 2008|Archive|

Chemo- and radiotherapy especially effective in HPV-linked oropharyngeal tumors

  • 5/28/2008
  • Ann Arbor, MI
  • staff
  • HemOncToday (www.hemonctoday.com)

Induction chemotherapy as a selection method for concurrent chemoradiotherapy was found to be an effective treatment method for advanced oropharyngeal cancer, and better response to the treatment was associated with the presence of human papilloma virus.

Previous research into the increasing incidence of oral/oropharyngeal tumors has indicated HPV as an etiologic factor. Although some reports suggest that HPV-positive individuals with these tumors have better outcomes, the reports have not been unanimous. Researchers at the University of Michigan Comprehensive Cancer Center in Ann Arbor tested the efficacy of induction chemotherapy followed by concurrent chemoradiotherapy or surgery/radiotherapy and assessed the effect of HPV on response and outcome.

Study design

The study included 66 patients (51 men) with stage III to IV squamous cell carcinoma of the oropharynx. Patients were treated with one cycle of cisplatin (100 mg/m2) or carboplatin (AUC 6) as well as 5-fluorouracil (1,000 mg/m2 per day for five days). This regimen was used as a selection method for those eligible for chemoradiotherapy: patients who achieved a greater than 50% response at the primary tumor received chemoradiotherapy. Patients with a complete histologic response were given adjuvant paclitaxel. Pretreatment biopsies of 42 patients were tested for high-risk HPV.

Fifty-four of the 66 patients (81%) achieved the 50% response rate and 53 of these patients received chemoradiotherapy. Among those 53 patients, 49 (92%) achieved a complete histologic response with a 73.4% rate of organ preservation. The four-year overall survival rate was 70.4% with a disease-specific survival rate of 75.8%. The median time to follow-up was 64 months.

HPV16 was found in 27 of the 42 patients tested (64.3%). It was associated with a younger age (median, 55 years vs. 63 years; P=.016), sex (22 of 30 men vs. five of 12 women; P=.08) and nonsmoking status (P=.037). HPV copy number was found to be significantly associated with patients’ response to induction chemotherapy (P=.003). It also had a positive effect on overall survival (HR=0.81; 95% CI 0.70-0.94) and on disease-free survival (HR=0.77; 95% CI 0.63-0.93).

HPV status and response

Of the 27 HPV-positive patients, 25 were responders to induction chemotherapy and 24 were responders to chemoradiotherapy. Of the 15 HPV-negative patients, 10 responded to induction chemotherapy and seven of those 10 responded to chemoradiotherapy. The positive associations between HPV and response and survival were maintained after adjusting for variables including sex, smoking status, T class, N class, age and primary tumor site.

Francis Worden, MD, an assistant professor of internal medicine at the University of Michigan, said that this research further separates oropharyngeal tumors based on etiology. “The biggest challenge is how best to treat patients with tumors that stem from tobacco and alcohol use as opposed to tumors linked to HPV,” he said in a press release. “We now know they’re two different cancers.” – by Dave Levitan

For more information:
Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008;10.1200/JCO.2007.12.7597.

May, 2008|Archive|

Gene Therapy Increases Survival for End-Stage Head and Neck Cancer

  • 5/28/2008
  • Houston, TX
  • staff
  • newswise.com

A gene therapy invented at The University of Texas M. D. Anderson Cancer Center is the first to succeed in a U.S. phase III clinical trial for cancer, as announced today at the American Society of Gene Therapy annual meeting in Boston.

Introgen Therapeutics, Inc., reported results of its phase III trial of Advexin®, a modified adenovirus that expresses the tumor-suppressing gene p53, for end-stage head and neck cancer.

“Cells become cancerous because p53 no longer functions. Restoring p53 works unlike any current cancer treatment because it treats the cancer genome,” said Jack Roth, M.D., professor in M. D. Anderson’s Department of Thoracic & Cardiovascular Surgery, who invented the drug and co-founded Introgen. He remains a shareholder and paid consultant to Introgen, and the University of Texas System is also a shareholder in Introgen.

The p53 gene is inactivated in many types of cancer. Its normal role is to halt the division of a defective cell and then force the cell to kill itself.

The trial showed that p53 expression in the patient’s tumor before treatment is a reliable biomarker for how to treat head and neck cancer. Patients with a favorable p53 profile who received Advexin® had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53 before treatment. Patients with this unfavorable profile were better off taking the chemotherapy drug methotrexate, resulting in median survival of 5.9 months.

“The important finding is that patients who benefit from treatment can be identified with the p53 biomarker. The biomarker will enable physicians to personalize treatment,” said Roth, who also directs M. D. Anderson’s W.M. Keck Center for Innovative Cancer Therapies.

Detailed results of the 123-patient clinical trial, led by John Nemunaitis, M.D., executive director of the Mary Crowley Medical Research Center at Baylor-Charles A. Sammons Cancer Center in Dallas, are available at http://www.introgen.com.

Better Quality of Life

Patients treated with Advexin® experienced far fewer harmful side effects such as pneumonia than those who received methotrexate. The incidence of inflammation of the mouth lining and a decrease in white blood cells, for example, both dropped to zero for those receiving Advexin®.

“That certainly results in a better quality of life,” Roth noted, which makes sense because p53 does not cause problems in normal cells.

Roth’s lab has been developing gene therapy for cancer since 1990. “We wanted to go beyond conventional treatment, because most of those treatments were not very effective,” Roth said. “Surgery and radiation are limited to the local tumor and once given, it’s very hard to repeat those therapies. Chemotherapy inhibits DNA replication, but it also interferes with normal cells.”

From idea to Phase I Trial at M. D. Anderson

All basic and preclinical work on the modified adenovirus was done at M. D. Anderson. The first phase I clinical trial was conducted by Gary Clayman, M.D., D.D.S., professor in M. D. Anderson’s Department of head and neck surgery. Clayman also enrolled patients in the phase II and phase III clinical trials conducted by Introgen.

Roth and colleagues deleted an important region of the adenovirus’ genome, preventing it from replicating. They installed a genomic segment that expresses p53. When injected into a tumor, the p53 adenovirus burrows into the cancer cell’s nucleus. But instead of replicating in a typical viral manner, it expresses p53, resulting in cell death.

Clayman’s phase I trial provided the first indicator that p53 expression in the tumor before treatment could be an accurate biomarker for p53 therapy. The concept was further developed retrospectively in Introgen’s phase II trial, Roth said, and then it was applied prospectively in the phase III trial, with results related to biomarker status blinded until final data analysis.

If a tumor expresses high or low levels of normal p53, or a very low level of mutant p53, conditions are favorable for Advexin®. Tumors with high levels of mutant p53 do not respond well to p53-related therapy. The healthy and mutant p53 biomarkers are easily discerned with standard lab techniques, Roth said immunohistochemical staining detects protein levels, while gene chip analysis reveals gene sequence.

Creation of Introgen

Roth found little interest in gene therapy from established pharmaceutical companies, so in 1994 he co-founded Introgen working through M. D. Anderson’s Office of Technology Management.

Introgen has since grown into a publicly traded company on NASDAQ, and while it still licenses important technology from M. D. Anderson, the company works broadly with other medical research institutions and biotech firms.

Introgen developed a commercial-grade version of the drug and advanced it through phase II and III clinical trials for head and neck cancer. Advexin® also is being tested in other cancers in a variety of clinical trials.

“If something’s going to get to patients, it has to be commercialized,” Roth said. The National Cancer Institute funds basic and translational research but simply cannot afford to fund large, late-stage clinical trials, he said.

Nanotechnology and p53

Roth and colleagues now focus on ways to deliver p53 and other tumor-suppressing genes systemically – through intravenous delivery. Advexin® has to be injected straight into the tumor, but that’s not workable for many cancers. Head and neck cancer kills patients by recurring, not spreading to other organs, but most cancer deaths involve metastasis.

By wrapping tumor-suppressing genes in tiny balls of fat, Roth and colleagues hope to be able to treat more invasive cancers. While p53 nanoparticles are still in preclinical development, those that deliver another tumor-suppressor called FUS1 are in a phase I clinical trial for non-small cell lung cancer. Through 19 patients, the dose escalation study has yet to encounter significant side effects.

Injected nanoparticles gather mainly in tumors, where they are taken up and dissolved, leaving the tumor-suppressor gene at work in the cell. A version that combines FUS1 and p53 is under development.

Nanoparticle research is funded by a National Cancer Institute Specialized Programs in Research Excellence (SPORE) grant to Roth and John Minna, M.D., of the Department of Internal Medicine and Pharmacology, Hamon Center for Therapeutic Oncology Research, at The University of Texas Southwestern Medical Center at Dallas. This team also discovered the FUS1 gene. FUS1 and p53 nanoparticles also are licensed to Introgen.

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 39 Comprehensive Cancer Centers designated by the National Cancer Institute. For five of the past eight years, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News and World Report.

May, 2008|Archive|

Photodynamic therapy for head and neck cancer

  • 5/26/2008
  • Tokyo, Japan
  • T Yoshida et al
  • Diagn Ther Endosc, January 1, 1996; 3(1): 41-51

Photodynamic therapy (PDT) is a recently developed treatment involving the use of a photosensitizer and low power light, usually from a laser, to selectively destroy tumor cells. At present, we perform PDT for head and neck cancer using argon or excimer dye lasers with hematoporphyrin derivative as a photosensitizer. This study attempted to assess the utility and safety of PDT and to investigate the long-term outcome.

All 24 patients had squamous cell carcinoma: 15 with laryngeal, 5 with lingual or oral, and 4 with pharyngeal cancer and were treated by PDT. Data were obtained from records from February 1988 through April 1995. After PDT, 12 of 15 laryngeal cancer patients were classified as having a complete remission (CR), as were 2 of the 5 lingual or oral and one of the 4 pharyngeal cancer patients. The patients were followed for 8 to 153 months. The longest duration of CR in patients treated by PDT alone was 148 months. Photosensitivity was experienced by all patients, but required no treatment. Liver, kidneys, and bone marrow showed no abnormal values. There were no clinically relevant adverse reactions, and patients with severe complications due to other types of treatment and elderly patients were also treated safely with this therapy.

Authors:
T Yoshida, H Kato, T Okunaka, T Saeki, S Ohashi, T Okudaira, AM Lee, H Yoshida, H Maruoka, H Ito, and S Funasaka

Authors’ affiliation:
Department of Otolaryngology, Head and Neck Surgery Tokyo Medical College 6-7-1 Nishishinjuku, Shinjuku-ku Tokyo 160 Japan

May, 2008|Archive|

A randomized, placebo-controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer

  • 5/26/2008
  • Omaha, NE
  • WM Lydiatt et al.
  • Arch Otolaryngol Head Neck Surg, May 1, 2008; 134(5): 528-35

Objective:
To determine whether prophylactic treatment with the antidepressant citalopram hydrobromide, compared with placebo, could prevent major depressive disorder in patients undergoing therapy for head and neck cancer (HNC).

Design:
Prospective, randomized, placebo-controlled trial.

Setting:
Academic medical center.

Patients:
Thirty-six subjects were randomized, and 23 completed the study.

Interventions:
Subjects were randomized to receive 40 mg of citalopram hydrobromide or matching placebo (herein after, citalopram group and placebo group, respectively) for 12 weeks with a final visit at 16 weeks.

Main Outcome Measures:
The Hamilton Depression Rating Scale, psychiatric interview, and the University of Washington Quality of Life (UW-QOL) and Clinician Global Impression-Severity (CGI-S) scales.

Results:
The numbers of subjects who met predefined cutoff criteria for depression during the 12 weeks of active study were 5 of 10 (50%) taking placebo and 2 of 12 (17%) taking citalopram (Fisher exact test, P = .17). No patients in the citalopram group became suicidal, compared with 2 in the placebo group. Global mood state at the conclusion of the study as measured by the CGI-S scale was rated as at least mildly ill in 15% of those receiving citalopram compared with 60% in the placebo group (Fisher exact test, P = .04). Quality of life, measured by the UW-QOL, deteriorated in both groups from baseline but less so in the citalopram group.

Conclusions:
This study reports data from the first depression prevention trial in HNC and suggests that prophylactic treatment may decrease the incidence of depression during HNC therapy. The clinical significance of the reduction in depression was best demonstrated by the CGI-S scale, which showed a notable difference in global psychiatric and physical well-being.

Authors:
WM Lydiatt, D Denman, DP McNeilly, SE Puumula, and WJ Burke

Authors’ affiliation:
Department of Otolaryngology-Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE

May, 2008|Archive|

Alcohol gene linked to mouth cancer

  • 5/26/2008
  • Aberdeen, Scotland
  • staff
  • The Press Association (ukpress.google.com)

Scientists have discovered a link between mouth cancer and the genes which break down alcohol, it was revealed.

A major international study found people’s risk of developing oral cancer was related to genes which regulate how fast or slowly alcohol was metabolised by the body.

Researchers at the University of Aberdeen spent five years studying hundreds of patients with cancers of the mouth, larynx and oesophagus at centres throughout Europe and Central and South America.

They also studied patients who were free of the disease.

The study focused on two genes involved in metabolising alcohol – a substance which is already known to be a risk factor for oral cancer.

The academics found those with a variant in the genes appeared to be less susceptible to the cancers because alcohol was broken down more quickly.

Dr Tatiana Macfarlane, senior lecturer at the University of Aberdeen’s department of general practice and primary care, said: “The study showed that your risk of getting oral cancers is linked to genetics as well as lifestyle.

“We found that, in particular, the risk depends on how fast your body metabolises alcohol.

“The results suggest that the faster you metabolise it, the lower your risk.

“These results provided the strongest evidence yet that alcohol consumption is strongly linked to oral cancers. The risk is particularly high if you also smoke or rarely eat fruit and vegetables.”

May, 2008|Archive|

Medical Researchers Urged to Speed Up Vaccine’s Safety Investigations

The Oral Cancer Foundation is urging medical researchers to speed up investigations on the safety of a vaccine for a sexually transmitted virus that it said causes cancer of the mouth.

The foundation’s statement comes shortly after studies published this month in the medical journal “Cancer” and the New England Journal of Medicine, which suggest a link between human papillomavirus (HPV) and oral cancer.

Currently, the vaccine—which protects against four strains of the virus—is administered to girls and adolescent females to protect against cervical cancer, the foundation said.

Deaths from cervical cancer, which number about 3,700 per year nationally, have declined due to improved methods of early detection and the public’s greater awareness of the importance of annual screenings, the foundation said.

The foundation also said men can benefit if given the same vaccine and urged the FDA to approve such a use once scientific due diligence has been accomplished.

“The study affirms what we have long believed, namely that the vaccine can reduce oral cancer rates if given to both males and females,” said Brian Hill, founder and executive director of the Oral Cancer foundation.

Oral cancer can be detected early through simple visual and hand examinations, the foundation said. But no public awareness campaign exists nationally to promote detection, it said.

Every day in the United States, 93 people develop oral cancer—and one person dies from it every hour, more than twice the death rate of cervical cancers and higher than many of the more commonly known cancers, according to the foundation.
Compounding the problem is that oral cancer often goes unnoticed in its early stages and it usually not detected until later, when prognosis is poor, the foundation said.

Rates of oral cancer are on the rise nationally, despite years of declining tobacco use, the foundation said.

“What seems like a paradox actually illuminates the expanding role HPV- 16 plays in acquiring this disease,” Hill said.

HPV-16 is one of the destructive strains out of more than 100 versions of the virus, the foundation said. It was first linked to oral cancer more than 10 years ago, but recent research has backed up claims about its role as a causative factor in oral cancer in both men and women, the foundation said.

HPV, which can be transmitted either through genital or oral-genital contact, is the most common sexually transmitted disease in the United States, the foundation said.

About 20 million men and women currently have the disease, and close to 80 percent of sexually active adults will acquire the virus at some point in their lives, the foundation said.

Hill said widespread use of the vacine in both men and women will result in positive collateral benefits in reducing rates of oral cancer.

He also warned that delaying research and subsequent FDA approvals could come at a cost in higher oral cancer rates.

May, 2008|OCF In The News|