Long Term Ozone Exposure Raises The Risk Of Dying From Lung Disease
24/4/2009 ·
Long-term exposure to elevated levels of ground ozone a major constituent of smog significantly raises the risk of dying from lung disease, according to a new nationwide study of cities that evaluated the impact of ozone on respiratory health over an 18-year period.
The study found that the risk of dying from respiratory disease is more than 30 percent greater in metropolitan areas with the highest ozone concentrations than in those with the lowest ozone concentrations.
Over the last decade, several nationwide studies have shown that long-term exposure to tiny particles of dust and soot in air pollution is a risk factor for death from heart and lung disease. However, it was unclear whether long-term exposure to ozone, a widespread pollutant in summertime haze, was linked to a higher risk of dying from lung disease itself.
The new study, published in the March 12 issue of the New England Journal of Medicine, is the first nationwide population study on the long-term impact of ozone on human health, and the first to separate ozone's effects from those of fine particulate matter, the tiny particles of pollutants emitted by factories, cars, and power plants.
"Many studies have shown that a high-ozone day leads to an increase in risk of acute health effects the next day, for example, asthma attacks and heart attacks," says George D. Thurston, Sc.D. who directed the air pollution exposure assessment part of the study. "What this study says is that to protect the public's health, we can't just reduce the peaks, we must also reduce long-term, cumulative exposure." Dr. Thurston is a professor in the Department of Environmental Medicine at NYU School of Medicine, a part of NYU Langone Medical Center.
Ozone in the upper atmosphere protects against harmful ultraviolet (UV) radiation. At ground level, ozone, or O3, forms when nitrogen dioxide from tailpipes, coal-fired power plants and other industries collides with oxygen in the presence of sunlight. Considered a secondary pollutant because it takes time to form, ozone tends to be higher in concentration in suburbs and rural areas downwind of cities. Fine particulate matter, a primary pollutant, is more prevalent at its source, in the inner city, along roadways and in industrial areas.
In concert with rising death rates from respiratory disease, "background levels of ozone have at least doubled since pre-industrial-revolution times," says Michael Jerrett, Ph.D., associate professor, Division of Environmental Health Sciences, at the University of California, Berkeley, and the lead author of the new study.
The study analyzed data on some 450,000 people who were followed from 1982 to 2000 as part of an American Cancer Society study. Over that period 118,777 people in the study died. The data, which included cause of death, were linked to air pollution levels in 96 cities using advanced statistical modeling to control for individual risk factors, such as age, smoking status, body mass, and diet, as well as for regional differences among the study populations.
By statistically controlling for the other major component of smog fine particulate matter, particles smaller than 2.5 microns the researchers were able to tease out the cardiovascular impact of the pollutants and still see ozone's effects on respiratory health.
Ozone data collected between 1977 and 2000 showed that California had both the city with the highest and the city with the lowest concentration of ozone pollution in the country. The researchers estimate that the risk of dying from respiratory causes rises 4 percent for every 10 parts-per-billion increase in exposure to ozone. Based on that result, Dr. Thurston says the city with the highest mean daily maximum ozone concentration over the 18-year period of the study, was Riverside (104 ppb). This long-term cumulative exposure corresponded to roughly a 50 percent increased risk of dying from lung disease compared to no exposure to the pollutant. Los Angeles ran a close second, with an estimated 43 percent increased risk.
Northeast cities were generally lower in ozone than California. In Washington, DC, and New York City, for example, the study results indicate a 27 and 25 percent increased risk of respiratory death, as a result of their respective long-term ozone exposures, says Dr. Thurston. The estimated increased risk from cumulative exposure in New York occurs even though New Yorkers breathe air that is nearly in compliance with the EPA's present short-term ozone standard of 75 ppb, he says.
The lowest ozone concentration was seen in San Francisco (33 ppb long-term average daily maximum), which had an associated 14 percent increase in risk. San Francisco has low levels of ozone pollution because fog regularly blankets the city, which prevents the necessary photochemical reaction from occurring, says Dr. Jerrett. In addition, Dr. Thurston points out that the Los Angeles area, which has high levels, is located in a basin, which prevents the rapid dispersal and dilution of air pollution that occurs in San Francisco.
The present EPA air quality standards do not protect against the long-term cumulative effects of ozone exposures, but only address the health effects of short-term daily peaks in ozone exposure, says Dr. Thurston. Currently, the Environmental Protection Agency's standard for short-term (8-hour) ozone exposure is 75 parts per billion, which exceeds the 60 ppb recommended by the EPA's own scientific advisory group, the American Lung Association and more than a dozen other public health organizations. The EPA will be reviewing its ozone standard in the coming year.
"How do we lower the burden of disease?" queries Dr. Thurston. "Do we look only at only those affected by the highest days, or do we look at everyone's exposure over the entire year? Since we all share the same air, paying attention to cumulative exposure shifts the whole exposure distribution for us all, and that's where the health payoff is. A small reduction in everybody's year-round risk benefits us all."
The other co-authors of this study are: Kazuhiko Ito from the NYU School of Medicine; Arden Pope from Brigham Young University; Richard Burnett from Health Canada, the federal health department based in Ottawa; Daniel Krewski and Yuanli Shi from University of Ottawa; Michael Thun and the late Eugenia Calle from the American Cancer Society in Atlanta.
About NYU Langone Medical Center
Located in the heart of New York City, NYU Langone Medical Center is one of the nation's premier centers of excellence in health care, biomedical research, and medical education. For over 167 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; the three hospitals of NYU Hospitals Center, Tisch Hospital, a 726-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care; and such major programs as the NYU Cancer Institute, the NYU Child Study Center, and the Hassenfeld Children's Center for Cancer and Blood Disorders.
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Preclinical Data Presented On ARIAD's Investigational MTOR Inhibitor, Deforolimus, In Lung Cancer And Other Solid Tumor Models
23/4/2009 ·
"The single-agent activity of deforolimus observed in preclinical models provides a compelling rationale for our recently initiated Phase 2 clinical trial of deforolimus in patients with non-small cell lung cancer whose tumors have a KRAS mutation. These results are particularly important considering the limitations of available treatments for such patients," said Timothy P. Clackson, Ph.D., senior vice president and chief scientific officer of ARIAD. "In addition, the data on deforolimus in combination with Merck's IGF-1R inhibitor, MK-0646, confirm the rationale for using these two investigational drugs together in diverse types of solid tumors. Our ongoing Phase 1 trial of this combination represents an important opportunity for our oncology partnership."
Deforolimus in Non-Small Cell Lung Cancer with KRAS Mutation
Deforolimus demonstrated potent single-agent, anti-tumor activity in preclinical models of non-small cell lung cancer with a KRAS mutation.
Approximately 20 percent of non-small cell lung tumors have KRAS mutations, and these tumors typically do not respond well to EGFR inhibitors, such as erlotinib. In a panel of more than one hundred lung-cancer cell lines, deforolimus showed greater inhibition of tumor growth than erlotinib in 79 percent of cell lines tested and 84 percent of KRAS mutant cell lines. Further, deforolimus potently inhibited the growth of erlotinib-resistant, KRAS-mutant tumors in three different mouse models.
These data lend support for the choice of patients with advanced non-small cell lung cancer whose tumors have a KRAS mutation as the target population for study in the ongoing randomized, double-blind, placebo-controlled Phase 2 clinical trial of oral deforolimus.
Deforolimus and MK-0646 Combination
Deforolimus in combination with Merck's anti-IGF-1R monoclonal antibody, MK-0646, licensed from Pierre Fabre Medicament, led to more effective pathway targeting and anti-tumor activity than with either investigational agent alone in several preclinical models.
The insulin-like growth factor-1 receptor (IGF-1R) is activated in many tumor types, leading to tumor-cell proliferation. IGF-1R functions, in part, through activation of mTOR. In the research presented, a genetic screen identified mTOR and IGF-1R as complimentary drug targets. Testing in panels of cell lines and mouse models showed that combined treatment with these two investigational agents can provide significantly enhanced anti-tumor activity. The mechanism of this dual effect was confirmed as "vertical-pathway synergy" and blocking of feedback signaling between IGF-1R and mTOR.
These data support the ongoing Phase 1 study of oral deforolimus combined with MK-0646 in patients with advanced solid tumors, which is designed to evaluate the hypothesis of vertical-pathway synergy by inhibiting two targets in the PI3K-Akt-mTOR pathway. This multicenter study is aimed at determining the safety profile, tolerability and recommended doses for use in subsequent trials of the combination regimen.
About Deforolimus
ARIAD's lead product candidate, deforolimus, is a novel rapamycin analog that specifically and potently inhibits mTOR, a downstream activator of the PI3K/Akt and nutrient sensing pathways. The mTOR protein acts as a "master switch" in cancer cells. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis. Multiple Phase 1 and Phase 2 clinical trials of deforolimus in solid tumors and hematologic cancers have been completed, or are in the process of patient enrollment. The global Phase 3 SUCCEED trial of oral deforolimus in metastatic soft-tissue and bone sarcomas is based on a Special Protocol Assessment agreed upon by the U.S. Food and Drug Administration. ARIAD has a global partnership with Merck & Co., Inc. to develop and commercialize deforolimus in patients with cancer.
About ARIAD
ARIAD's vision is to transform the lives of cancer patients with breakthrough medicines. The Company's mission is to discover, develop and commercialize small-molecule drugs to treat cancer in patients with the greatest and most urgent unmet medical need - aggressive cancers where current therapies are inadequate. ARIAD's lead product candidate, deforolimus, is an investigational mTOR inhibitor in Phase 3 clinical development in patients with advanced sarcomas and is being developed in collaboration with Merck & Co., Inc. ARIAD's second product candidate, AP24534, is an investigational multi-targeted kinase inhibitor in Phase 1 clinical development in patients with hematological cancers. ARIAD has an exclusive license to pioneering technology and patents related to certain NF-κB cell-signaling activity, which may be useful in treating certain diseases. For additional information about the Company, please visit http://www.ariad.com.
This press release contains "forward-looking statements." Forward-looking statements are based on management's expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. These risks and uncertainties include, but are not limited to, preclinical data and early-stage clinical data that may not be replicated in later-stage clinical studies, the costs associated with our research, development, manufacturing and other activities, the conduct, timing and results of pre-clinical and clinical studies of our product candidates, the adequacy of our capital resources and the availability of additional funding, and other factors detailed in the Company's public filings with the U.S. Securities and Exchange Commission. The information contained in this press release is believed to be current as of the date of original issue. The Company does not intend to update any of the forward-looking statements after the date of this document to conform these statements to actual results or to changes in the Company's expectations, except as required by law.
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Genetic Source Of Rare Childhood Cancer Found; Gene Is Implicated In Other Cancers
23/4/2009 ·
The search for the cause of an inherited form of a rare, aggressive childhood lung cancer has uncovered important information about how the cancer develops and potentially sheds light on the development of other cancers.
The finding by researchers at Washington University School of Medicine in St. Louis, Children's National Medical Center in Washington, D.C., the International Pleuropulmonary Blastoma Registry at Children's Hospitals and Clinics of Minnesota, and other collaborating institutions adds the final link to the chain connecting the gene DICER1 to cancer development something that had been suspected but until now not definitively demonstrated.
The results were presented April 19, 2009, at the 100th Annual Meeting of the American Association of Cancer Research in Denver. The study shows that some children with the rare cancer pleuropulmonary blastoma (PPB) are born with a deleterious mutation in DICER1, a master controller gene that helps regulate the expression of other genes. The children studied came from families with a history of PPB or related disorders.
"PPB is the first malignancy found to be directly associated with inherited DICER1 mutations, making the cancer an important model for understanding how mutations and loss of DICER1 function lead to cancer," says lead author D. Ashley Hill, M.D., chief of pathology at Children's National Medical Center. "Additionally, we now believe that PPB tumors arise from an unusual mechanism in which cells carrying mutations induce nearby cells to become cancerous without becoming cancerous themselves."
Hill was principal investigator of the study, which began while she was on the Washington University faculty.
Only 50 to 60 cases of PPB are diagnosed each year around the world. Most children with PPB are under five years old. The cancer progresses from air-filled lung cysts in the early stage to solid lung tumors in later stages. If detected in the earliest stage, 90 percent of patients can be cured when treated with surgery and sometimes chemotherapy. Overall survival drops to about 40 percent if the cancer is diagnosed in the latest stage.
The researchers found that all the children studied with PPB carried damaging mutations in one of their DICER1 genes, giving them one functional and one nonfunctional DICER1 gene in all their body's cells. The researchers indicate that PPB lung tumors probably originate when one or more cells in the lung acquire a harmful mutation in their functional copy of the DICER1 gene.
The researchers also found that PPB lung tumors appear to result from a novel cancer induction mechanism not previously demonstrated. They discovered that loss of DICER1 protein specifically in lung airway cells appears to deregulate signals to nearby cells and somehow causes those cells to transform into malignant cells. However, the cells with the loss of DICER1 do not progress to malignancy.
DICER1 is so-named because its job is to chop up large molecules into smaller control molecules that help regulate the output of many of the 30,000 human genes. The short bits of genetic material it produces during its dicing activities are termed microRNAs.
"Prior research showed that the microRNA profiles of cancer cells are different from those of normal tissue, which pointed toward a possible role for DICER1 in cancer," says senior author Paul Goodfellow, Ph.D., co-director of the Hereditary Cancer Core at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "Very recently, other research found that reduced DICER1 gene expression in tumor cells is associated with worse outcomes in patients with ovarian, lung, breast and prostate cancers. Now we've shown that mutations in the DICER1 gene are directly linked to the development of PPB."
"For years, our large collection of cases of PPB and families has revealed the strong genetic component of this disease," says Jack Priest, M.D., research director of the International PPB Registry in Minnesota. "We are thrilled that our colleagues Dr. Hill and Dr. Goodfellow uncovered an important mutation and have begun to understand the cellular mix-up that results in malignancy."
Current studies show that about 40 percent of PPB cases occur in families with a history of the disease or certain other childhood cancers. Most pediatric cancers occur sporadically, without any familial patterns. This led scientists and doctors to suspect that PPB was caused by an inherited genetic abnormality. To uncover the role of DICER1, the research team studied the genetic makeup of 11 extended families with two or more members having PPB or related childhood cancers.
The scientists say that finding this variant form of a gene in some PPB families is a first step to understanding why PPB and other conditions may occur in some families. But, because only a small number of families were studied it isn't known whether DICER1 mutations explain all PPB cases, and much more needs to be learned before this information can be directly helpful to PPB families.
In collaboration with Hill and Goodfellow, and with Louis P. Dehner, M.D., professor of pathology and immunology at Washington University School of Medicine, who first described PPB in 1988, the International PPB Registry in Minnesota has collected and analyzed PPB cases from around the world for more than 20 years. More than 260 confirmed cases are being followed. The registry is funded by Minneapolis/St. Paul-area foundations and is the only organization in the world focused exclusively on PPB.
Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, WikenHeiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. Germline DICER1 mutations in familial pleuropulmonary blastoma. Presented at the 100th Annual Meeting of the American Association of Cancer Researcher, April 19, 2009.
Funding from the Siteman Cancer Center, the Children's Discovery Institute at St. Louis Children's Hospital and Washington University School of Medicine, the Hope Street Kids Foundation, the Foundation of Children's Hospitals and Clinics of Minnesota, the Pine Tree Apple Tennis Classic, the Washington University Department of Pathology, St. Louis Children's Hospital Foundation and the Urological Research Foundation supported this research.
About Washington University School of Medicine and the Siteman Cancer Center Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.
About Children's National Medical Center/Children's Research Institute
Children's National Medical Center is the only exclusively pediatric provider of care in the metropolitan Washington, D.C., area. Its team of pediatric healthcare professionals cares for more than 360,000 patients each year from throughout the region, nation and world. Serving as an advocate for all children, Children's provides millions of dollars in uncompensated care annually. In addition, Children's serves as the regional referral center for pediatric emergency, trauma, cancer, cardiac and critical care as well as neonatology, orthopaedic surgery, neurology, and neurosurgery. Children's National is ranked consistently among the best pediatric hospitals in America by U.S. News & World Report and the Leapfrog Group.
About Children's Hospitals and Clinics of Minnesota
Serving as Minnesota's children's hospital since 1924, Children's Hospitals and Clinics of Minnesota is the seventh -largest pediatric health care organization in the United States, with 332 staffed beds at its two hospitals in St. Paul and Minneapolis. An independent, not-for-profit health care system, Children's of Minnesota provides care through more than 14,000 inpatient visits and more than 200,000 emergency room and other outpatient visits every year. Children's is the only Minnesota hospital system to provide comprehensive care exclusively to children, and in 2008 was ranked among the best pediatric hospitals by U.S. News & World Report.
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Poniard Announces Publication Of Results Of Picoplatin Phase 2 Study In Journal Of Clinical Oncology
23/4/2009 ·
Poniard Pharmaceuticals, Inc. (Nasdaq: PARD), a biopharmaceutical company focused on oncology, announced that results of its Phase 2 clinical trial of picoplatin in patients with recurrent small cell lung cancer (SCLC) were published in the April 20, 2009, print issue of the Journal of Clinical Oncology(1). Picoplatin demonstrated a survival benefit in this open-label, multi-center Phase 2 trial of SCLC patients who failed prior platinum-containing first-line chemotherapy or who progressed within six months of first-line therapy. The median overall survival was 27 weeks and the median one-year survival rate was 17.6 percent in this patient population of mostly platinum-refractory and -resistant patients.
Poniard is currently evaluating the efficacy and safety of picoplatin in the pivotal Phase 3 SPEAR (Study of Picoplatin Efficacy After Relapse) SCLC trial, which is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). The Company reached its enrollment target in this international, multi-center, randomized, controlled trial in March 2009.
SCLC is the most aggressive lung cancer and tends to be widely disseminated by the time of diagnosis. The prognosis for patients with SCLC that has progressed despite chemotherapy is exceedingly poor regardless of stage. Effective second-line treatment for SCLC is a major unmet need. There is no standard chemotherapy for second-line platinum-refractory or -resistant SCLC.
"New treatments are desperately needed for patients with platinum-resistant and -refractory small cell lung cancer due to the rapid relapse of the disease and the slim chance that patients will experience long-term survival," said John Eckardt, M.D., lead author of the JCO publication, picoplatin clinical trial investigator, and chief medical officer of DAVA Oncology. "I am encouraged that picoplatin extended survival in this patient group and was generally well tolerated. Data from the Phase 3 SPEAR trial in the same patient population will further clarify the potential of picoplatin as a viable treatment for patients with this highly lethal type of cancer."
Phase 2 Study Design and Results
The open-label, multi-center Phase 2 trial was designed to confirm the clinical activity and safety of picoplatin as second-line therapy in patients with platinum-refractory disease or platinum-resistant or platinum-sensitive disease that had progressed within six months after first-line treatment with a platinum-based chemotherapy, such as cisplatin or carboplatin. Efficacy endpoints included response rates, progression-free survival, overall survival, improvement in disease-related symptoms and disease control (defined as complete response, partial response and stable disease). The trial was conducted at clinical sites in North America and Eastern Europe.
A total of 77 patients received picoplatin. Median overall survival was 27 weeks following picoplatin administered once every three weeks. Median progression-free survival was 9 weeks. The six-month and one-year survival rates were 51 percent and 17 percent, respectively. The disease control rate was 47 percent in the 77 evaluable patients. The most common side effects observed were hematologic and included thrombocytopenia, neutropenia and anemia. No grade 3 or 4 neurotoxicity or nephrotoxicity and no treatment-related deaths occurred in the study.
"The publication of these clinical findings in JCO represents an important milestone for Poniard. The positive survival results of the Phase 2 picoplatin trial in this difficult-to-treat disease formed the basis of our decision to initiate the Phase 3 SPEAR trial for which we recently completed patient enrollment ahead of internal projections," said Robert De Jager, M.D., chief medical officer of Poniard. "We are on track to complete the clinical data analysis of the SPEAR trial and initiate the filing of a rolling New Drug Application with the FDA for picoplatin in SCLC this year. If approved, picoplatin could represent an important new treatment for SCLC. In addition, it potentially enables other trials of picoplatin in patients with other solid tumors who relapse or are refractory to first-line platinums, such as in non-small cell lung cancer and ovarian cancer."
About Picoplatin
Picoplatin is designed to overcome platinum resistance associated with chemotherapy in solid tumors. Study data to date indicate that it has an improved safety profile relative to existing platinum-based cancer therapies. More than 1,100 patients have been treated with picoplatin. Results obtained to date suggest manageable hematologic adverse events with less severe kidney toxicity (nephrotoxicity) and nerve toxicity (neurotoxicity) than is commonly observed with other platinum chemotherapy drugs. Picoplatin has demonstrated anti-tumor activity in a variety of solid tumors. It is being studied in multiple cancer indications, treatment combinations and by two routes of administration.
The SPEAR trial is comparing picoplatin plus best supportive care, to best supportive care alone, to evaluate the efficacy and safety of picoplatin after relapse in SCLC patients. The primary efficacy endpoint is overall survival. Progression-free survival, overall response rate, and disease control are also being evaluated. The Company is currently evaluating picoplatin in two Phase 2 clinical trials -- one is evaluating the safety and efficacy of picoplatin in patients with metastatic colorectal cancer and the other in patients with castration-resistant (or hormone-refractory) prostate cancer. Oral picoplatin is being evaluated in a Phase 1 clinical trial in solid tumors.
About Poniard Pharmaceuticals
Poniard Pharmaceuticals, Inc. is a biopharmaceutical company focused on the development and commercialization of innovative oncology products to impact the lives of people with cancer.
This release contains forward-looking statements, including statements regarding the Company's results of clinical trials, business objectives and strategic goals, drug development plans, the potential safety and efficacy of its products in development and commercialization strategy. The Company's actual results may differ materially from those indicated in these forward-looking statements based on a number of factors, including risks and uncertainties associated with the Company's research and development activities; the results of clinical testing; the receipt and timing of FDA and other required regulatory approvals; the market's acceptance of the Company's proposed products; the Company's anticipated operating losses, need for future capital and ability to obtain future funding; competition from third parties; the Company's ability to preserve and protect intellectual property rights; the Company's dependence on third-party manufacturers and suppliers; the Company's lack of sales and marketing experience; the Company's ability to attract and retain key personnel; changes in technology, government regulation and general market conditions; and the risks and uncertainties described in the Company's current and periodic reports filed with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 10-K for the year ended December 31, 2008. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. The Company undertakes no obligation to update any forward-looking statement to reflect new information, events or circumstances after the date of this release or to reflect the occurrence of unanticipated events.
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Encouraging Results Published On Use Of TomoTherapySM In Lung Cancer Treatment
22/4/2009 ·
TomoTherapy Incorporated (NASDAQ: TOMO) cited recently published encouraging preliminary results of an ongoing Phase I clinical trial on the use of intensity-modulated (IMRT) and image-guided radiation therapy (IGRT) focusing on the concept of accelerated hypofractionation to overcome tumor repopulation, one of the well-known mechanisms of radiation resistance, using TomoTherapySM for non-small cell lung cancer (NSCLC).
The paper, published in Technology in Cancer Research and Treatment (Technol Cancer Res Treat. 2008 Dec;7(6):441-8.) titled, "Dose Escalated, Hypofractionated Radiotherapy Using Helical Tomotherapy for Inoperable Non-Small Cell Lung Cancer: Preliminary Results of a Risk-Stratified Phase I Dose Escalation Study," evaluates a study devised to test the safety of escalating the biologically-effective tumor dose via hypofractionated treatment regimens using 25 fractions over five weeks. Traditionally, radiotherapy is delivered over six to seven weeks, or even longer (sometimes up to 10-11 weeks) if dose-escalation is the goal. A downside to dose escalation in this manner is that tumor repopulation occurs during the prolonged delivery time. Shorter dose-escalated schedules have historically been avoided because of the expectation of severe toxicities. The University of Wisconsin (UW) School of Medicine and Public Health investigators hypothesized that the conformal dose-delivery abilities of TomoTherapy, with helical IMRT and IGRT, would permit safe dose-escalation with shorter schedules, thereby limiting accelerated repopulation, and possibly improving tumor control.
According to its authors, the study demonstrates that the use of TomoTherapy technology may allow for higher doses of radiation therapy than are conventionally administered to be delivered over a shorter treatment course, with lower than expected toxicities. Helical TomoTherapy allows for delivery of image-guided, intensity-modulated radiation therapy, permitting conformal delivery of radiotherapy while minimizing the dose delivered to normal tissues.
"The early results of this study suggest that a hypofractionated schedule with dose-escalation can safely be achieved and, although preliminary, the survival data look promising," said senior author Minesh Mehta, M.D., radiation oncologist and professor of Human Oncology at the UW School of Medicine and Public Health. "Preliminary results suggest that better tumor control and possible survival improvement may be achieved safely with this method, compared retrospectively with traditional radiotherapy techniques."
Calculations predicting the likelihood of lung toxicity, along with constraints on maximum esophageal and spinal cord dose, were used to help customize the total dose and dose per fraction given to each patient. Doses between 57 and 80.5 Gy were delivered in fraction doses of 2.28-3.22 Gy, representing equivalent doses in 2 Gy fractions of 60-100 Gy.
Promising Preliminary Results:
- For the 46 patients in the study, 80% of whom had stage III NSCLC, overall survival 2 years after treatment was 46.8%. Stage-for-stage, this compares with a 2-year survival rate of 21.5% from a database representing all clinical, surgical-pathologic, and follow-up information for 5,319 patients treated for primary lung cancer.
- Higher doses of radiation therapy than are conventionally administered (typically ~60 Gy in 2 Gy fractions) may be delivered safely in a hypofractionated schedule with helical TomoTherapy. Reported lung and esophageal toxicities are lower than expected from previous dose escalation studies using conventional radiotherapy technology.
- No patient experienced grade 3 or higher pneumonitis. Grade 2 pneumonitis occurred in only 13% of patients in this study. This illustrates one of the major safety parameters of the study.
- No patients experienced grade 3 esophagitis. For those developing esophagitis of grade 1 (24% of patients) or grade 2 (13%) an average weight loss of under 3% occurred. In a University of Michigan dose-escalation study utilizing 3-D radiotherapy, and a non-hypofractionated approach to dose-escalation, grade 1, 2, and 3 esophagitis occurred in 39.5%, 16.5% and 2.7% of patients respectively. The esophageal dose constraints used in the protocol have since been relaxed, given the low incidence of significant esophagitis.
- Statistical analysis showed that mean dose to normal lung is a predictor of the rate of lung pneumonitis, but that dose prescribed to the tumor is not. This indicates that the methodology for safe dose prescription based on predicted normal tissue toxicity is valid. The maximum tolerated dose has not been reached and the protocol continues to accrue patients.
Says Rock Mackie, Ph.D., founder and chairman of TomoTherapy and a UW School of Medicine professor, "While it's still early in the process, we are pleased and encouraged that the results of the study demonstrate that treatment can be delivered in higher doses and in shorter periods of time. This is a promising result which makes us hopeful that there will be improvement in the way non-small cell lung cancer responds to treatment and can be managed moving forward."
About University of Wisconsin School of Medicine and Public Health
The University of Wisconsin School of Medicine and Public Health is a comprehensive research and teaching facility in Madison Wisconsin, and is home to the UW Paul P. Carbone Comprehensive Cancer Center (UWCCC). Helical tomotherapy was conceived and developed by faculty and staff of the UWCCC and UW School of Medicine and Public Health Departments of Human Oncology and Medical Physics.
About TomoTherapy Incorporated
TomoTherapy Incorporated has developed, markets and sells the TomoTherapy® Hi•Art® treatment system, an advanced radiation therapy system for the treatment of a wide variety of cancers. The Hi•Art treatment system combines integrated CT imaging with conformal radiation therapy to deliver sophisticated radiation treatments with speed and precision while reducing radiation exposure to surrounding healthy tissue. The company's stock is traded on the NASDAQ Global Select Market under the symbol TOMO. To learn more about TomoTherapy, please visit http://www.TomoTherapy.com.
Forward-Looking Statements
Statements in this release regarding future results, expectations, events and other similar matters, including but not limited to statements using the terms "suggest", "demonstrates" and "may" constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All such forward-looking statements are based on current expectations and are subject to risks and uncertainties. Should any of these risks or uncertainties materialize, or should any of the Company's assumptions prove incorrect, actual results may differ materially from those included within these forward-looking statements. Accordingly, no undue reliance should be placed on these forward-looking statements, which speak only as of the date made. TomoTherapy assumes no obligation to update or revise the forward-looking statements in this release because of new information, future events or otherwise.
©2009 TomoTherapy Incorporated. All rights reserved. TomoTherapy, Tomo, the TomoTherapy logo and Hi•Art are among trademarks, service marks or registered trademarks of TomoTherapy Incorporated in the United States and other countries.
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