The study builds on the success of a previous clinical trial at M. D. Anderson that included surgery called extra pleural pneumonectomy (EPP), which involves removal of the affected lung and lining of the chest, followed by a highly specialized form of radiation therapy known as Intensity Modulated Radiotherapy (IMRT).
The new multi-center study, which will recruit 77 patients nationwide, will involve EPP, post-operative IMRT and the chemotherapy drugs pemetrexed (Alimta®) and cisplatin, says Katherine Pisters, M.D., principal investigator on the study at M. D. Anderson and associate professor in the Department of Thoracic/Head and Neck Medical Oncology.
Memorial Sloan-Kettering Cancer Center, New York
University of Chicago, Chicago
Johns Hopkins Hospital, Baltimore
Barbara Ann Karmanos Cancer Institute, Detroit
University of Pennsylvania, Philadelphia
Brigham and Women's University, Boston
Many of the sites already have begun studying the use of chemotherapy prior to surgery and radiation. The chemotherapy combination of pemetrexed and cisplatin was approved by the Food and Drug Administration (FDA) for treatment of mesothelioma after the drugs were shown to prolong survival.
Answering questions about both studies are Pisters, Craig Stevens, M.D., Ph.D., principal investigator on the previous M. D. Anderson trial and associate professor in the Division of Radiation Oncology; and David Rice, M.D., surgical principal investigator on the new study and assistant professor in the Department of Thoracic and Cardiovascular Surgery.
What is unique about this study?
Pisters: This is the first mesothelioma trial to explore the use of chemotherapy before surgery and radiation.
How does the new trial build on the previous study?
Stevens: Our previous trial involving extrapleural pneumonectomy and IMRT was more than 90% effective in preventing a local recurrence (return of the cancer to its original site). However, 50% of those patients experienced recurrence in a different location, usually the other lung, abdomen or another part of the body. M. D. Anderson will be the only center employing IMRT rather than conventional radiation therapy.
Pisters: We are now adding chemotherapy before surgery and radiation to decrease the possibility of distant cancer metastasis (spread to an area away from the original site). We are using pemetrexed and cisplatin because they already have been shown to be effective in metastatic disease.
How has this chemotherapy been found effective?
Stevens: Pemetrexed and cisplatin were shown to prolong survival by three months in mesothelioma patients with advanced disease (when the drugs were taken together, compared to if cisplatin was taken alone).
What does each component of the trial involve?
Stevens:
Pemetrexed (Alimta®) and cisplatin - Chemotherapy drugs given before surgery.
Extrapleural pneumonectomy (EPP) - Surgery to remove the lung, lining of the chest, diaphragm and pericardium, which is the sac that contains the heart. The diaphragm and pericardium are reconstructed with prosthetic material.
Intensity Modulated Radiotherapy (IMRT) - High-precision radiation that delivers multiple beams of radiation to tumors or areas within a tumor. This technique can deliver radiation to very irregularly-shaped targets, like those found after EPP. Other centers involved in this study will use more conventional forms of radiation.
What are the benefits of this surgery?
Rice: The only thing that has ever been shown to lead to any long-term survival has been extrapleural pneumonectomy followed by some form of post-operative treatment, usually radiation alone or a combination of chemotherapy and radiation.
Why is it necessary to remove the lung and other organs?
Rice: Mesothelioma starts in the parietal pleura (the lining of the inner chest wall and lining that covers the diaphragm) and grows into the visceral pleura (lining that covers the lung). It is almost impossible to separate the visceral pleura from the lung in order to remove the cancer, so the lung must be removed. In addition, mesothelioma frequently invades the lung tissue, so for complete removal of the tumor, the lung must be removed.
The tumor usually abuts the diaphragm and pericardium, so to completely remove all of the cancer we have to remove those structures. Then we reconstruct the diaphragm and the pericardium. It is a big operation and takes anywhere from four to six hours. Patients undergo the operation only after careful pre-operative evaluation that involves surgical staging (minor surgical procedures to determine the extent of the disease), as well as careful testing of lung and heart function. The staging done in the first trial was important because it eliminated 12% of the patients who were ineligible for surgery due to advanced disease.
Stevens: The other reason to remove the lung and diaphragm is to prevent breathing motion of the radiation targets. Accounting for such motion is very difficult. Accounting for the motion incorrectly will lead to more tumor recurrence.
What is life like for people with one lung?
Rice: It is very difficult to predict. Most people have a mild to moderate degree of shortness of breath (also one of the symptoms of the disease before surgery.) Because the surgery involves a very large incision and we occasionally have to take portions of the ribs out, many patients have a fair amount of pain immediately after surgery. But we are usually able to control it well with pain medication.
Sometimes, particularly with patients who have excruciating pain related to the tumor growing through the chest wall, if we can get that tumor out, the pain does improve. Paradoxically, some patients seem to breathe even better after we remove their affected lung. The reason for this is probably relief of tumor compression on the lung and the associated restriction of chest wall movement.
What was the survival rate in the previous trial?
Stevens: Out of 55 patients, we had only one infield failure (cancer returning within an area that received radiation). Most of our patients are more than two years out from treatment. In comparison, most patients without radiation have an 80% fail rate within nine months. With more "conventional" radiation approaches, about one of three patients fail in the irradiated regions.
How was IMRT able to be as precise as it was in the previous trial?
Stevens: During EPP, the surgeon implants titanium clips in the chest to mark the areas where mesothelioma tumors are located. We can see the clips on X-ray and can then pinpoint where the cancer was and irradiate that area with IMRT. The clips are critical, and the way the diaphragm is reconstructed is really important. The diaphragm is reconstructed with Gore-Tex®, a material that we can see on X-ray that allows us to better tailor the radiation beam to that patient. During surgery the (reconstructed) diaphragm is pulled tight so that the abdominal contents are pushed as far out of the radiation field as possible.
How many cases of mesothelioma will be treated in the United States this year?
Rice: There are expected to be approximately 3,500 cases, but that number will increase and peak in the next several years because of asbestos controls in the 1970s and the 20- to 40-year period between the time asbestos exposure begins and mesothelioma develops. It also is not clear how large amounts of asbestos released during the World Trade Center disaster will impact future mesothelioma incidences.
Although we have an estimation of the number of people who will be diagnosed with mesothelioma, it is not known exactly how many of those patients will be actually treated because there is probably a large number of patients with mesothelioma who are misdiagnosed as having metastatic adenocarcinoma (another form of cancer).
In addition, there is generally a nihilistic attitude about this disease in the medical community, and it is likely that many patients are not referred to centers where potentially curative treatment may be given.
Although we are far from having a cure for all patients with mesothelioma, the recent development of more effective chemotherapeutic agents, radical surgery and advanced radiotherapeutic modalities now at least offers a glimmer of hope to patients suffering from this devastating disease.
For more information about the new mesothelioma study at M. D. Anderson involving pemetrexed and cisplatin, EPP and IMRT, contact research nurses Li Ling Hwang or Jean Riddle in the Department of Thoracic/Head and Neck Medical Oncology at (713) 792-6363.
Courtesy of Cancer Wise
]]>If the malignant mesothelioma is in one part of the chest lining, treatment will probably be surgery to remove the part of the chest lining with cancer and some of the tissue around it.
If localized malignant mesothelioma is found in more than one place in the chest, treatment may be one of the following:
Pleurectomy and decortication, with or without radiation therapy, as palliative therapy to relieve symptoms and improve the quality of life.
Extrapleural pneumonectomy.
Radiation therapy as palliative therapy to relieve symptoms and improve the quality of life.
A clinical trial of anticancer drugs placed directly into the chest after surgery to remove the tumor.
A clinical trial of combinations of surgery, radiation therapy, and chemotherapy.
A clinical trial of a new treatment.
Advanced Malignant Mesothelioma (Stage II, Stage III, and Stage IV)
Treatment of advanced malignant mesothelioma may include the following:
Surgery to drain fluid that has collected in the chest, to reduce discomfort. Pleurodesis may be done to stop more fluid from collecting in the chest.
Pleurectomy and decortication, as palliative therapy to relieve symptoms and improve the quality of life.
Radiation therapy as palliative therapy to relieve pain.
Chemotherapy with one anticancer drug.
A clinical trial of combination chemotherapy.
A clinical trial of combinations of surgery, radiation therapy, and chemotherapy.
A clinical trial of chemotherapy placed directly into the chest cavity or abdominal cavity to shrink the tumors and keep fluid from building up.
This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NCI Web site.
Recurrent Malignant Mesothelioma
Treatment of recurrent malignant mesothelioma may include the following:
A clinical trial of biologic therapy.
A clinical trial of chemotherapy.
A clinical trial of surgery.
This summary section refers to specific treatments under study in clinical trials, but it may not mention every new treatment being studied. Information about ongoing clinical trials is available from the NATIONAL CANCER INSTITUTE Web site.
Patients with advanced cancer who used an implantable drug-delivery device to control their pain had better pain relief, fewer toxic side effects, and better survival than patients who received intensive medical pain management, researchers reported in the October 1, 2002, issue of the Journal of Clinical Oncology.
The multicenter trial involved 202 patients who were randomly assigned to two groups. One group received comprehensive medical management (CMM) for their pain. CMM is a more systematic approach to pain control than cancer patients typically receive. It involves a team of health care professionals with special training in pain management who search for the most effective pain medication for each patient by starting with the least toxic and only gradually moving up to medications with more side effects until the pain is relieved. CMM may also include the use of complementary methods of pain reduction such as relaxation, guided imagery, psychotherapy, and patient support groups.
Upon entering the study, most trial participants were taking at least 250 milligrams per day of narcotic pain relievers, such as morphine. Many were also taking additional medications such as antidepressants and anticonvulsants for pain relief.
During the study, patients in the CMM-only group continued to take morphine or similar narcotic drugs by mouth, plus additional medications as needed. Most IDDS patients received morphine via the pump; the others received hydromorphone (Dilaudid). IDDS patients could take additional narcotics by mouth if necessary.
At study entry, all trial participants rated their pain as well as the side effects of their pain medication (such as sedation, clouded thinking, constipation, and fatigue) on scales from 0 (least) to 10 (worst). Both the CMM-only group and the CMM-plus-IDDS group had average pain scores of more than 7.5 at the start of the trial.
But four weeks later, pain scores for IDDS patients fell to an average of 3.7 (a 51.5 percent reduction). In CMM patients, average pain scores dropped to 4.8 (a 39 percent reduction). IDDS patients also experienced a 50 percent reduction in toxic side effects after four weeks. By contrast, in patients who received CMM alone, toxic side effects declined by 17 percent.
When the researchers looked to see how many individuals in each group lowered their pain and side-effects scores by 20 percent or more, they found that 58 percent of patients using the implantable device had achieved this level of relief compared with 38 percent of patients who received CMM alone.
Survival rates also differed. After six months, 54 percent of patients using the implantable device were alive, compared with 37 percent of those in the CMM-only group. The better survival among users of the implantable device may be partly explained by the fact that they experienced a larger reduction in toxic side effects, say the investigators, who were led by Thomas J. Smith, M.D., of the Medical College of Virginia in Richmond.
As many as 15 percent of cancer patients have pain that is not relieved by conventionally delivered narcotic pain medications, note the researchers. Previous studies have shown that fear of the side effects of these medications is an important reason why many doctors fail to prescribe them and many patients decline to take them.
"This is a well-designed study that shows a modest but real benefit from the use of an implantable pump for control of cancer pain," commented Mitchell Max, M.D., a pain control specialist at the National Institute of Dental and Craniofacial Research in Bethesda, Maryland. He added, however, that it is premature to conclude that implantable pumps are better for all patients with difficult-to-treat cancer pain. "We need more research to better define which subgroups of cancer patients will benefit the most from using these devices."
Experimental Cancer Drug Tarceva
Reuters, October 9, 2002
NEW YORK (Reuters Health) - OSI Pharmaceuticals Inc. is more confident than ever of the potential of its experimental cancer drug Tarceva (erlotinib HCl), even after the failure of a similar drug in a major clinical study this summer, OSI Chairman and CEO Dr. Colin Goddard told investors at the UBS Warburg Global Life Sciences conference here on Wednesday.
In August, AstraZeneca Plc. announced that adding its investigational non-small cell lung cancer (NSCLC) drug Iressa to standard therapy did not improve survival in a phase III trial of patients who had failed prior chemotherapy. The news raised concerns about a new class of cancer drugs expected to be effective with fewer side effects than other therapies.
Iressa is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. These kinds of drugs are believed to cause fewer adverse events because they target specific proteins associated only with tumors.
Since Tarceva is also an EGFR inhibitor, many industry watchers began to worry that the drug, which is still being evaluated in a phase III trial of NSCLC patients, might also fail to meet expectations.
But Dr. Goddard dismissed these concerns on Wednesday, noting that while similar, Iressa and Tarceva are structurally different. But more importantly, he said, the companies' approaches in evaluating their respective drugs are very different, as well.
Dr. Goddard told Reuters Health that in its failed trial, AstraZeneca was using doses of Iressa one-third to two-thirds of the maximum tolerable dose. OSI is using the highest tolerated dose of Tarceva.
Interestingly, he said, one of the side effects of Tarceva treatment is rash, and "what we find is when we produce rash, patients tend to do very well. In other words, there's a suggestion that pushing dose has real benefit in terms of survival."
"Hence, our whole rationale and belief is that we will see a differentiation between [Iressa and Tarceva] on the basis of that [dosing] strategy."
The OSI study is expected to complete patient accrual by the end of the year. Dr. Goddard said that OSI expects Tarceva to receive a six-month priority review by the US Food and Drug Administration after it is submitted.
Chemotherapy Combination Promising For Mesothelioma
Journal of Clinical Oncology, August 13, 2002
LONDON (Reuters Health) Aug 13 - A new chemotherapy combination has shown "remarkable" activity against mesothelioma in an early study, British researchers reported on Tuesday. Malignant pleural mesothelioma is increasing in incidence in most countries and has shown a poor response to systemic chemotherapy, the investigators write in their report, published in the Journal of Clinical Oncology for August 13. Approximately 250,000 people are expected to die from the disease in Western Europe over the next 35 years, they note. But the combination of a new drug called pemetrexed, developed by Eli Lilly, with carboplatin could be an effective treatment for the hard-to-treat condition, Dr. Hilary Calvert from Newcastle General Hospital and colleagues say.
The researchers administered the two drugs to 27 patients with malignant pleural mesothelioma in a Phase I dose-escalating study.
"The drug combination showed remarkable activity in mesothelioma," Professor Calvert said in a news release. "Indeed, our study provided the first convincing demonstration that pemetrexed [and] carboplatin could be useful in the treatment of the disease." Of 25 patients who completed the study, 8 showed a partial response, while 70% of patients noticed an improvement in symptoms, often after just 2 courses of chemotherapy. The median survival time in the study was 451 days, or over 14 months. A handful of patients have survived for 3 years or more. Previously, people diagnosed with mesothelioma could expect to survive for 6 to 8 months, the University of Newcastle said. The chemotherapy triggered neutropenia, leukopenia and thrombocytopenia, but these toxicities were usually short-lived and "caused few clinical problems," the researchers write.
A multinational, randomized trial has since shown an improvement of survival and symptoms, according to the news release.
"Mesothelioma is a serious condition that is difficult to treat, so this is an important development," Dr. Lesley Walker, director of cancer information at Cancer Research UK said in the news release. "We now need to look closely at the drug's performance in the next stages of clinical trials to see how it compares to other anti-cancer drugs."
Chemotherapy Combination Promising For Mesothelioma
Journal of Clinical Oncology, August 13, 2002
LONDON (Reuters Health) Aug 13 - A new chemotherapy combination has shown "remarkable" activity against mesothelioma in an early study, British researchers reported on Tuesday. Malignant pleural mesothelioma is increasing in incidence in most countries and has shown a poor response to systemic chemotherapy, the investigators write in their report, published in the Journal of Clinical Oncology for August 13. Approximately 250,000 people are expected to die from the disease in Western Europe over the next 35 years, they note. But the combination of a new drug called pemetrexed, developed by Eli Lilly, with carboplatin could be an effective treatment for the hard-to-treat condition, Dr. Hilary Calvert from Newcastle General Hospital and colleagues say.
The researchers administered the two drugs to 27 patients with malignant pleural mesothelioma in a Phase I dose-escalating study.
"The drug combination showed remarkable activity in mesothelioma," Professor Calvert said in a news release. "Indeed, our study provided the first convincing demonstration that pemetrexed [and] carboplatin could be useful in the treatment of the disease." Of 25 patients who completed the study, 8 showed a partial response, while 70% of patients noticed an improvement in symptoms, often after just 2 courses of chemotherapy. The median survival time in the study was 451 days, or over 14 months. A handful of patients have survived for 3 years or more. Previously, people diagnosed with mesothelioma could expect to survive for 6 to 8 months, the University of Newcastle said. The chemotherapy triggered neutropenia, leukopenia and thrombocytopenia, but these toxicities were usually short-lived and "caused few clinical problems," the researchers write.
A multinational, randomized trial has since shown an improvement of survival and symptoms, according to the news release.
"Mesothelioma is a serious condition that is difficult to treat, so this is an important development," Dr. Lesley Walker, director of cancer information at Cancer Research UK said in the news release. "We now need to look closely at the drug's performance in the next stages of clinical trials to see how it compares to other anti-cancer drugs."
Experimental Therapy
Several forms of mesothelioma treatment such as the drug Alimta, gene therapy, immunotherapy, photodynamic therapy and multimodality therapy are still in their experimental stages. We invite you to read the following articles on experimental therapies for Malignant Mesothelioma.
Drug Therapy
Alimta, a new type of cancer treatment being developed by Eli Lilly, is the first treatment to significantly increase the length of survival and ameliorate the symptoms of the disease. The trial, one of the largest against the fatal disease, was presented at the annual meeting of the American Society of Clinical Oncologists.
Click here to browse through drug therapy related medical literature, articles and abstracts.
Gene Therapy
Many strategies of gene therapy are currently under study. Even though the results in animal experiments have been remarkable they have remained disappointing in humans. Other agents such as onconase, thalidomide, lovastatin have been used as single therapy or in combination with chemotherapy with various results.
Click here to browse through gene therapy related medical literature, articles and abstracts.
Immunotherapy
This therapy involves the removal of patient cells, activation by exposure to cytokines and reinstillatin into the peritoneum, accompanied by additional chemotherapy. In the few cases tried this form of treatment lead to significant shrinkage of the tumor. However most patients had very early stages of disease, and general recommendations are therefore difficult to make, prior to further research.
Photodynamic Therapy
This therapy involves the use of a drug that makes the cancer cells sensitive to a particular wavelength of light. The drug is administered before the surgical procedure. The results have been disappointing, and no survival benefit has been shown in studies so far.
Click here to browse through photodynamic therapy related medical literature, articles and abstracts.
Multimodality Therapy
Doctors are always learning more about the best way to treat patients with mesotheliomas. The roles of surgery, radiation therapy, and chemotherapy in the treatment of mesothelioma are highly debated. Treatments which use some combinations of surgery, radiation therapy, and chemotherapy, called multimodality therapy, are now being studied and may provide the most promising option for some patients.
This information is provided courtesy of The National Cancer Institute.
]]>Dana E. M. Rollison1, William F. Page2, Harriet Crawford2, Gloria Gridley3, Sholom Wacholder3, Jennifer Martin4, Richard Miller2 and Eric A. Engels3
1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
2 Medical Follow-up Agency, Institute of Medicine, the National Academies, Washington, DC.
3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Rockville, MD.
4 RTI International, Rockville, MD.
Simian virus 40 (SV40) was an accidental contaminant of vaccines produced in monkey kidney tissue cultures in the 1950s and early 1960s, including a parenteral adenovirus vaccine given to several hundred thousand US military recruits. Detection of SV40 DNA in tumor tissues by some laboratories suggests that SV40 contributes to human cancers. To determine if entry into US Army service during periods of administration of SV40-contaminated adenovirus vaccine was associated with an increased risk of cancer, the authors conducted a case-control study of cancer occurring in male Army veterans who entered service in 1959-1961.
]]> Cases of brain tumors (n = 181), mesothelioma (n = 10), and non-Hodgkin's lymphoma (n = 220) were identified through a Veterans Administration hospital discharge database, as were colon cancer and lung cancer controls (n = 221). Exposure to adenovirus vaccine was assigned on the basis of known periods of adenovirus vaccine administration and dates of Army entry obtained for cancer cases and controls. The odds ratios associated with exposure to SV40-contaminated adenovirus vaccine were 0.81 (95% confidence interval (CI): 0.52, 1.24) for brain tumors, 1.41 (95% CI: 0.39, 5.15) for mesothelioma, and 0.97 (95% CI: 0.65, 1.44) for non-Hodgkin's lymphoma. These findings do not support a role for SV40 in the development of these cancers.
brain neoplasms; lymphoma, non-Hodgkin; mesothelioma; military personnel; simian virus 40; United States Department of Veterans Affairs
Abbreviations: Abbreviations: BIRLS, Beneficiary Identification and Records Locator Subsystem; CI, confidence interval; ICD, International Classification of Diseases; OR, odds ratio; PTF, Patient Treatment File; SV40, simian virus 40.
Key Words: chemotherapy, lung cancer, mesothelioma, pemetrexed. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Researchers with the largest phase III trial to date for mesothelioma, an aggressive cancer affecting the lining of the lung, reported results showing that patients on a new chemotherapy drug regimen live longer and have less pain than those on an older drug. The findings were announced at the annual meeting of the American Society of Clinical Oncology meeting in Orlando, Fla., on May 20, 2002. (NOTE: The final data were subsequently published in the July 15, 2003, issue of the Journal of Clinical Oncology; see the journal abstract).
]]> Pemetrexed (brand name Alimta‚Ñ¢) is a novel antifolate, a class of drugs that targets the folic acid metabolic pathway, which effects availability of certain B complex vitamins. The results of the trial show that tumors shrank in 41 percent of patients on pemetrexed in combination with a more commonly used chemotherapy agent called cisplatin. Only 17 percent of patients receiving cisplatin alone experienced tumor shrinkage. Additionally, those on the pemetrexed combination lived nearly three months longer than those on cisplatin alone.According to lead author, Nicholas J. Vogelzang, M.D., University of Chicago Cancer Research Center, "This is the largest clinical trial ever conducted in this disease and the 25 to 30 percent improvement in survival for patients on the combination therapy is the first time anyone has documented a significant improvement in patients treated for mesothelioma."
Malignant pleural mesothelioma is associated with a history of asbestos exposure in about 70 to 80 percent of all cases and there is no approved or very effective chemotherapy for the disease. Researchers hypothesized that pemetrexed might prove effective in treating this disease because it targets key enzymes (molecules that speed up chemical reactions in the body) thought to play a role in allowing the rapid growth of this tumor.
Early phase I trial results in 11 patients tested with pemetrexed and cisplatin were promising and a definitive randomized phase III trial was developed. Since there are no established therapies for this condition, a standard chemotherapy agent called cisplatin that has shown efficacy in treating other diseases, was used as the control group. The phase III study initially planned to enroll 456 patients from April 1999 to March 2001. However, after enrolling 150 patients, a high rate of severe toxicity and death was associated with the pemetrexed and cisplatin arm of the trial. Elevated levels of homocysteine, a chemical byproduct that results when proteins are broken down in the blood, were found, which provided a basis for redesign of the trial to reduce the dangerous drug side effects.
Two hundred and eighty patients were enrolled to the revised protocol. Using a strategy to reduce drug side effects that has been successful in the past, this new protocol added folic acid to the regimen because pemetrexed as an antifolate agent reduces levels of this important vitamin. Folic acid was given prior to and during the trial, and vitamin B12 was given only during the trial. Both vitamins should boost folic acid levels, reduce homocysteine formation, and hence reduce toxicity to pemetrexed. "We now have a significantly less toxic regimen than the one we started with," said Vogelzang.
Because of the presumed importance of the vitamins to the study, the researchers examined not only the combination therapy versus the single drug therapy, but also looked at the results of patients on the vitamin supplements versus those early enrollees who had not initially received vitamins.
Standard treatment for malignant mesothelioma has been surgery. Surgical treatment rarely results in cure and long-term survival is unusual. Use of radiation therapy and/or chemotherapy following surgery has not improved survival for patients but radiation treatments may alleviate some pain associated with the disease.
Note that Alimta is the correct name for pemetrexed. It is sometimes mispelled as Altima, Alitma, Amilta, and Atilma.
Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma
Nicholas J. Vogelzang, James J. Rusthoven, James Symanowski, Claude Denham, E. Kaukel, Pierre Ruffie, Ulrich Gatzemeier, Michael Boyer, Salih Emri, Christian Manegold, Clet Niyikiza, Paolo Paoletti
From the University of Chicago Cancer Research Center, Chicago, IL; Eli Lilly and Company, Indianapolis, IN; US Oncology, Dallas, TX; Allgemeines Krankenhaus Harburg, Hamburg; Krankenhaus Großhansdorf, Großhansdorf; and Thoraxklinik-Rohrbach, Heidelberg, Germany; Institut Gustave Roussy, Villejuif, France; Royal Prince Alfred Hospital, Camperdown, Australia; and Hacettepe University Medical Faculty, Ankara, Turkey.
Purpose: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone.
Patients and Methods: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days.
Results: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm.
Conclusion: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.
Sunday June 4, 8:00 am ET
Alimta Also Shows Tolerability as Triplet Combination Treatment in First-Line Lung Cancer
ATLANTA, Data presented today at the 42nd American Society of Clinical Oncology (ASCO) annual meeting in Atlanta, Ga., affirms that ALIMTA® (pemetrexed), manufactured and marketed by Eli Lilly and Company, offers patients with advanced non-small cell lung cancer (NSCLC) similar overall survival as docetaxel (Taxotere®).
"The data mirror previously reported results and confirm the efficacy of Alimta versus docetaxel," said Filippo de Marinis, M.D., director of the Pulmonary-Oncology Unit at San Camillo-Forlanini High Specialization Hospitals in Rome, Italy, and one of the study's principal investigators. "Based on these data, and on its safety advantage, Alimta should be regarded as a standard of care for non-small cell lung cancer patients in the second-line setting."
Patients in both arms of the trial were given standard doses of therapy for NSCLC. On day one of a 21-day cycle, patients in the Alimta arm of the trial received Alimta (500 mg/m squared), which was supplemented with vitamin B12 and folic acid as per label instructions. A team of researchers led by Lilly discovered that this vitamin supplementation given with Alimta significantly reduces the frequency and severity of the drug's side effects without compromising its ability to kill cancer cells. Patients in the docetaxel arm were given a 75 mg/m squared infusion.
As previously reported, the incidence of severe neutropenia, a decrease in the number of white blood cells that increases the risk of infection, was five percent in the Alimta arm and 40 percent in the docetaxel arm, an eight-fold difference that was statistically significant (p= <0.001). The difference in the incidence of neutropenic fever and subsequent hospitalizations between the Alimta and docetaxel arms was also statistically significant: two percent for the Alimta patients compared to 13 percent for the docetaxel patients (p= <0.001).
In a third finding that reached statistical significance, the incidence of drug-related serious adverse events -- which include side effects that could lead to a life-threatening outcome, death or hospitalization -- was 10 percent for Alimta patients and 24 percent for docetaxel patients (p= <0.001).
The incidence of grades 3/4 Alanine Transaminase (ALT) -- a laboratory measurement of liver function -- was 1.9 percent in the Alimta arm, a rate
that was significantly greater than in the docetaxel arm (p=0.028). According to findings, the incidence of grades 3/4 ALT in the Alimta arm was transient.
Alimta Data in First-Line NSCLC
In addition to its role in the second-line treatment of NSCLC, Alimta is also being investigated as a potential option for the treatment of first-line and earlier stages of NSCLC. Data disseminated on an additional study presented at the ASCO meeting reported on a single cohort Phase II clinical study which evaluated the safety and efficacy of a triplet therapy in which bevacizumab (Avastin®) was added to the combination of Alimta plus carboplatin, a regimen which has been reported upon in published articles.(ii,iii) Preliminary findings of this study suggest that this triplet therapy can be delivered at full doses of each drug with limited toxicity for the first-line treatment of NSCLC.
"Alimta is a very valuable component of the Lilly Oncology franchise," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader for Lilly. "We are extremely pleased that data continue to demonstrate the ability of the combination of Alimta and a platinum agent like carboplatin to serve as a reliable chemotherapeutic foundation for the treatment of non-small cell lung cancer. We are confident that Alimta will continue to provide notable benefits for patients with thoracic cancers and have great hopes for its potential in other tumor types."
Alimta is currently being studied in combination with eleven targeted agents in NSCLC, including bevacizumab (Avastin®), erlotinib (Tarceva®), cetuximab (Erbitux®), bortezomib (Velcade®), Matuzumab, as well as enzastaurin, Lilly's own novel investigational compound.
Alimta is an antifolate, which interferes with a crucial process that allows cancer cells to reproduce and spread. Alimta was first approved by the U.S. Food and Drug Administration in 2004 for malignant pleural mesothelioma, a tumor of the linings of the lungs often associated with exposure to asbestos, and also for second-line treatment of NSCLC. In the two years since its first approval for marketing, Alimta has been approved in 71 countries for either NSCLC or mesothelioma, and has become the leader for these indications in most markets. The most common side effects when Alimta is used as monotherapy are disorders of the blood and lymphatic system, gastrointestinal disorders, fatigue, rash and desquamation.
About Non-Small Cell Lung Cancer
The most common type of lung cancer, non-small cell lung cancer (NSCLC) represents 75-80 percent of all lung cancers. NSCLC has five-tier staging, starting at 0 and rising to the severity of stage IV. NSCLC can spread through the lymphatic system, penetrating the chest lining, ribs, and the nerves and blood vessels that lead to the arm. The liver, bones and brain are potential targets if the cancerous cells enter the blood stream.
About ALIMTA®
Alimta was first approved by the US Food and Drug Administration in 2004 for second-line treatment of non-small cell lung cancer (NSCLC), and for malignant pleural mesothelioma. In the two years since its first approval for marketing, Alimta has been approved in 71 countries for either NSCLC or mesothelioma and has become the leader for these indications in most markets. Delivered via a 10-minute infusion, Alimta is an antifolate, which interferes with a crucial process that allows cancer cells to reproduce and spread. (i) Hanna N, Shepherd FA, Fossella FV, et al. Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients with Non-Small Cell Lung Cancer Previously Treated with Chemotherapy. Journal Clinical Oncology, Vol. 22, pp. 1589-1597; May 1, 2004.
(ii) Scagliotti GV, Kortsik C, Dark GG, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res. 2005 Jan 15;11 (2 Pt 1):690-6.
(iii) Zinner RG, Fossella FV, Gladish GW, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. Cancer. 2005 Dec 1;104(11):2449-56.
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SOURCE The Pacific Heart Lung & Blood Institute, Inc
People interested in taking part in a clinical trial should talk with their doctor. Information about clinical trials is available from the Cancer Information Service (CIS ) (see below) at 1-800-4-CANCER. Information specialists at the CIS use PDQ®, NCI's cancer information database, to identify and provide detailed information about specific ongoing clinical trials. Patients also have the option of searching for clinical trials on their own. The clinical trials page on the NCI's Cancer.gov Web site provides general information about clinical trials and links to PDQ.
**This information is provided courtesy of The National Cancer Institute.**
Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of HDACs in mesothelioma tumor cells from patients enrolled in this trial. Evaluation of the genes regulating proliferation and apoptosis (programmed cell death), as well as acetylation of histone and non-histone proteins, will be performed.
About Mesothelioma
As many as 3,000 new cases of malignant mesothelioma are expected to be diagnosed in the United States in 2006. Mesothelioma is a type of cancer arising from the cells, known as mesothelium, with the majority of cancers beginning in the chest cavity. The incidence of mesothelioma increases with age and is rarely diagnosed in patients under 55 years old. Although environmental exposure to certain chemicals and radiation are believed to play a role in the development of mesothelioma, exposure to asbestos is believed to be the main cause of mesothelioma. The five-year survival rate for mesothelioma is approximately 10%, with an average survival of one to two years following diagnosis.
About PXD101
PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, including 5-fluorouracil (5-FU), carboplatin, paclitaxel and Velcade® (bortezomib) for Injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.
PXD101 is currently being evaluated in multiple clinical trials as a potential treatment for multiple myeloma, T-cell lymphoma, and colorectal and ovarian cancers, either alone or in combination with anti-cancer therapies. In August 2004, CuraGen signed a Clinical Trials Agreement with the NCI under which the NCI will sponsor several clinical trials to investigate PXD101 for the treatment of various cancers, both as a single-agent and in combination chemotherapy regimens. In May 2005, TopoTarget announced the signing of a Cooperative Research and Development Agreement (CRADA) with the NCI to conduct pre-clinical and non-clinical studies on PXD101 in order to better understand its anti-tumor activity and to provide supporting information for clinical trials.
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Corporation (Nasdaq: ACEL) announced today that groundbreaking, independent new research findings show that the elusive molecular mechanism that asbestos uses to provoke lung cancer may have been identified. The research also found that ONCONASE(R) (ranpirnase) may be one of the most effective methods of treatment for mesothelioma and lung cancer caused by this mechanism, and may even reduce the incidence of these cancers in those exposed to asbestos.
Dr. Carbone and his colleagues found that asbestos triggers the release of TNF-Alpha (Tumor Necrosis Factor-Alpha), a pro-inflammatory cytokine critical to the functioning of both innate and adaptive immune responses. The release of TNF-Alpha sets in motion a biochemical chain of events that led to the protection of asbestos-damaged cells from death. The cells exposed to asbestos were found to have produced TNF-Alpha. This caused the activation of the NF-KappaB (Nuclear Factor-Kappa B) protein, a transcription factor, found in all cell types, that plays a critical role in regulating immune response. Ineffective regulation of NF-KappaB has been linked to cancer and other diseases. The activation of NF-KappaB protected asbestos-damaged cells against cell death. Because the damaged cells did not die, they could then go on to develop into a cancer.
The authors state that because of this novel understanding of the molecules and mechanisms involved in asbestos toxicity, new methods of prevention and treatment could be developed that specifically target the inflammatory pathway activated by TNF-Alpha and its target NF-KappaB. ONCONASE was one of only two drugs cited in the article as targeting these pathways. As such, the researchers concluded that ONCONASE holds promise to reduce the incidence of mesothelioma and lung cancer in asbestos-exposed cohorts (groups of patients).
"ONCONASE inhibits the same pathways that we have shown lead to mesothelial cell malignant transformation and mesothelioma. Therefore, we hope to test the possible efficacy of this drug to prevent mesothelioma in high risk cohorts. The minimal side effects of ONCONASE make this approach feasible," stated Dr. Carbone.
Zbigniew Darzynkiewicz, M.D., Ph.D., Director of the Brander Cancer Research Institute, New York Medical College and a member of Alfacell's Scientific Advisory Board, stated, "The mechanism by which ONCONASE produces these effects appears to involve suppression of induction of the survival genes triggered by anti-tumor agents in cancer cells. Indeed, in preclinical studies, ONCONASE was found to amplify the efficacy of several chemotherapy drugs."
Dr. Darzynkiewicz added, "Many other types of cancer utilize the same pathway as mesothelioma. As such, it is reasonable to expect that ONCONASE will have wide clinical application as an anti-cancer agent, with particular promise as an adjunct in chemotherapy or in radiotherapy in treatment regimens for many different tumor types."
"Eight years ago, we hypothesized on the role of TNF-Alpha and NF-KappaB in ONCONASE's mechanism of action (Deptala et al, International Journal of Oncology, July 1998; Potentiation of tumor necrosis factor induced apoptosis by ONCONASE)," Dr. Darzynkiewicz concluded. "It is exciting to see strong affirmation of that hypothesis today."
]]>Pemetrexed (brand name Alimta?) is a novel antifolate, a class of drugs that targets the folic acid metabolic pathway, which effects availability of certain B complex vitamins. The results of the trial show that tumors shrank in 41 percent of patients on pemetrexed in combination with a more commonly used chemotherapy agent called cisplatin. Only 17 percent of patients receiving cisplatin alone experienced tumor shrinkage. Additionally, those on the pemetrexed combination lived nearly three months longer than those on cisplatin alone.
According to lead author, Nicholas J. Vogelzang, M.D., University of Chicago Cancer Research Center, "This is the largest clinical trial ever conducted in this disease and the 25 to 30 percent improvement in survival for patients on the combination therapy is the first time anyone has documented a significant improvement in patients treated for mesothelioma."
Malignant pleural mesothelioma is associated with a history of asbestos exposure in about 70 to 80 percent of all cases and there is no approved or very effective chemotherapy for the disease. Researchers hypothesized that pemetrexed might prove effective in treating this disease because it targets key enzymes (molecules that speed up chemical reactions in the body) thought to play a role in allowing the rapid growth of this tumor.
Early phase I trial results in 11 patients tested with pemetrexed and cisplatin were promising and a definitive randomized phase III trial was developed. Since there are no established therapies for this condition, a standard chemotherapy agent called cisplatin that has shown efficacy in treating other diseases, was used as the control group. The phase III study initially planned to enroll 456 patients from April 1999 to March 2001. However, after enrolling 150 patients, a high rate of severe toxicity and death was associated with the pemetrexed and cisplatin arm of the trial. Elevated levels of homocysteine, a chemical byproduct that results when proteins are broken down in the blood, were found, which provided a basis for redesign of the trial to reduce the dangerous drug side effects.
Two hundred and eighty patients were enrolled to the revised protocol. Using a strategy to reduce drug side effects that has been successful in the past, this new protocol added folic acid to the regimen because pemetrexed as an antifolate agent reduces levels of this important vitamin. Folic acid was given prior to and during the trial, and vitamin B12 was given only during the trial. Both vitamins should boost folic acid levels, reduce homocysteine formation, and hence reduce toxicity to pemetrexed. "We now have a significantly less toxic regimen than the one we started with," said Vogelzang.
Because of the presumed importance of the vitamins to the study, the researchers examined not only the combination therapy versus the single drug therapy, but also looked at the results of patients on the vitamin supplements versus those early enrollees who had not initially received vitamins.
Standard treatment for malignant mesothelioma has been surgery. Surgical treatment rarely results in cure and long-term survival is unusual. Use of radiation therapy and/or chemotherapy following surgery has not improved survival for patients but radiation treatments may alleviate some pain associated with the disease.
Content's source: www.cancer.gov
Food and Agriculture Organization
of the United Nations
Distr.: General
11 January 2005
Rotterdam Convention on the Prior Informed
Consent Procedure for Certain Hazardous
Chemicals and Pesticides in International Trade
Chemical Review Committee
First meeting
Geneva, 11-18 February 2005
Item 7 (m) of the provisional agenda*
Inclusion of chemicals in Annex III of the Rotterdam Convention:
Review of notifications of final regulatory actions to ban
or severely restrict a chemical: chrysotile asbestos
Chrysotile asbestos
Note by the secretariat
The secretariat has the honour to provide, in the annex to the present note, the supporting documentation received from Australia in support of its notification of final regulatory action on chrysotile asbestos. A focused summary is attached in annex I to the note and a list of supporting documentation, including the web addresses of the documents, in annex II.
]]> Annex II. Introduction
(a) The events that led to the final regulatory action
Use of chrysotile asbestos has been severely restricted in Australia since 31 December 2003. The National Industrial Chemicals Notification and Assessment Scheme (NICNAS) conducted a review of chrysotile in 1995 and published the final report in February 1999. The Chrysotile Priority Existing Chemical (PEC) assessment included information on chemical and physical properties, uses, exposure, kinetics and metabolism, effects on experimental animals and in vitro test systems, and human health effects. It also includes a hazard assessment and classification, risk characterisation and management, and recommendations for safe use. The report is available on the NICNAS web site at: http://www.nicnas.gov.au/publications/CAR/PEC/PEC9/PEC9index.asp
(b) Significance of regulatory action, e.g. one use or many uses, level or degree of exposure
As a result of the recommendations made by NICNAS in its report on chrysotile the Australian National Occupational Health and Safety Commission (NOHSC) in March 2001, proposed a severe restriction on all forms of asbestos and specifically on chrysotile asbestos for all uses apart from certain specific time-limited exemptions. These restrictions came into effect on 31 December 2003. Since 1995, the use of chrysotile had been prohibited when used for manufacture of asbestos products.
(c) An overview of the regulatory system of the notifying country if relevant
Chemical regulation in Australia occurs through several governmental agencies at both the Commonwealth and State level. Generally, whilst the assessment and registration of chemicals occurs at the Commonwealth level, management of chemicals occurs at the State level. Thus, control of usage and sales is primarily the responsibility of the States and Territories. State and Territory legislation directed at improving the management of chemicals across their lifecycles complement the activities of each of the Commonwealth schemes. Each State has a system of chemicals management designed to control a chemical throughout its lifecycle. Fields covered by specific State and Territory legislation include occupational health and safety, environment protection, transport and waste.
NICNAS is the Australian Government regulator for industrial chemicals and is located in the Office of Chemical Safety, within the Health and Ageing portfolio. NICNAS assesses all industrial chemicals new to Australia and assesses those industrial chemicals already used (existing chemicals) on a priority basis, in response to concerns about their safety on health and environmental grounds. A 'weight of evidence' approach is adopted in the assessment of each chemical, taking into account all available information including published literature, unpublished data, public information and international assessments. Recommendations from the NICNAS PEC assessment reports can have an important bearing on regulatory action that may be implemented within Australia in the context of protecting the health of workers and the public, and protecting the environment. For instance, they may impact on national occupational exposure standards, hazard classification, health surveillance guidelines, labelling requirements, and the development of codes of practice.
The National Occupational Health and Safety Commission (NOHSC) is Australia's national body that leads and coordinates national efforts to prevent workplace death, injury and disease in Australia. NOHSC recommends various standards and guidelines which the States and Territories take up and incorporate into their laws.
(d) Scope of the regulatory action - precise description of the chemicals subject to the regulatory action
The prohibition of chrysotile, from 31 December 2003, was made via amendments to the Australian Customs Services laws declaring the various forms of asbestos as prohibited imports (subject to exemptions). No asbestos is mined now in Australia and no new mining activity would be allowed as the total ban relates to the use, export and import of asbestos in Australia. The forms of asbestos listed in table 1 are now banned from import by federal legislation and from use in workplaces by state/territory laws (subject to the exemptions).
Table 1: Forms of asbestos prohibited in Australia
Name CAS Number Synonym
Actinolite asbestos 77536-66-4
Amosite 12172-73-5 Brown asbestos
Anthophyllite asbestos 77536-67-5
Chrysotile 12001-29-5 White asbestos
Crocidolite 12001-28-4 Blue asbestos
Tremolite asbestos 77536-68-6
Uses of chrysotile asbestos in Australia have now been banned as a result of the regulatory action except for certain limited exemptions. These exemptions are:
- Compressed asbestos fibre gaskets for use with saturated steam, superheated steam, or with substances, which are classified as dangerous goods, incl. corrosive or flammable, and very toxic or toxic. Where compressed asbestos fibre gaskets are to be used with chlorine, the exemption applies for plants used in liquid chlorine service with design process conditions of -45 degrees Celsius and 1500 kPa pressure. Exemption until 31 December 2004 and, for use with chlorine, 31 December 2006.
- Any product consisting of a mixture of asbestos with a phenol formaldehyde resin or with a cresylic formaldehyde resin used in: vanes for rotary vacuum pumps; vanes for rotary compressors; or split face seals of at least 150 millimetres in diameter used to prevent leakage of water from cooling water pumps in fossil fuel electricity generating stations. Exemption until 31 December 2007.
- Diaphragms for use in electrolytic cells in existing electrolysis plants for chlor alkali manufacture. Exemption until 31 December 2006.
- For the Australian Defence Organisation to use chrysotile parts and components which the ADO considers to be mission critical, and where there is no known suitable, non chrysotile alternative. This exemption will be regulated in detail by the Safety Rehabilitation Compensation Commission. Exemption until 31 December 2007.
It is not known whether products in these exempted categories are currently used in Australia.
II. Risk evaluation
(a) Key findings of the national risk evaluation
Australia's risk assessment report focused on: the occupational, public health and environmental risks associated with current uses and applications of chrysotile in Australia. In particular, the assessment has focused on the importation of chrysotile for manufacture of friction products and gaskets together with the use of these products in a variety of 'down stream' industrial/occupational sectors. Also assessed was the use of chrysotile as an additive in a specialty epoxy resin adhesive.
This report was based on reports available in the scientific literature, reviews by overseas agencies (such as IARC), together with local exposure and use data provided by Australian industry. It covers occupational health and safety, public health considerations and the effect of the chemical on the environment, undertakes a hazard and risk assessment of chrysotile over those three areas and makes recommendations based on the risk evaluation.
The assessment found that in Australia, the mining of asbestos (all forms) ceased in 1983. Asbestos (all forms) has not been exported from Australia since 1984. Chrysotile is the only form of raw asbestos being imported into Australia (by 3 companies) and remained at approximately 1000-2000 tonnes per year from 1990 to 1999, Canada being the sole source of these imports. Imports of asbestos (assumed to be mainly chrysotile) products, particularly friction products and gaskets, do not appear to be declining. Asbestos is still present in the general Australian community from a range of past uses, which have been carried out for substantial periods of time. In Australia imports of raw chrysotile were used mainly in the manufacture of friction materials and compressed asbestos fibre (CAF) sheeting for gasket production with a small quantity being used in the manufacture of a 'non-sag' additive in an epoxy resin adhesive. All these uses, according to manufacturers, were being phased out. Brake linings and gaskets were found to be the main asbestos products imported for use in Australia, although most such products imported into Australia are asbestos-free.
(b) Summary of actual (or potential) human exposure and/or environmental fate
Human exposure assessment
Chrysotile can cause asbestosis, lung cancer and mesothelioma in humans and animals in a dose related manner. The Australia Mesothelioma Program reports that Australia has the highest incidence of mesothelioma in the world. The potency of chrysotile in relation to other forms of asbestos (crocidolite, amosite and tremolite) and whether asbestosis is a prerequisite for cancer is contentious, and hence, whether a level of exposure for chrysotile exists, below which there would be no risk to human health (i.e., an exposure threshold for carcinogenic effects). Linear extrapolation methodology was used to provide a conservative estimate of risk. Risk estimates for lung cancer in workers appear to be dependent on both cumulative exposure and the type of industry where exposure has occurred. NOHSC (NOHSC, 1995a) has estimated the lifetime risk of lung cancer, based on the best available epidemiological data (from friction products industries overseas) as up to 173 additional cancers per 100,000 workers exposed to a daily average of 1 chrysotile fibre per mL. Extrapolation for lower exposures provides lifetime risk estimates (per 100,000 population) of 86 and 17 for exposure to 0.5 and 0.1 f/mL, respectively, although estimates by US NIOSH and OSHA are between 4 and 30 times higher (Lash, 1997; Stayner et al 1997). There are many confounding factors surrounding risk estimates for chrysotile exposure, the most important of which are; the possibility of a threshold effect, possible co-exposure to other fibre types, inaccurate estimates of historical exposures and the influence of tobacco smoking.
Workers: Exposures of most concern are those where friable chrysotile may be generated. Occupational exposure may arise from the manufacture of CAF sheeting and other products (mainly friction products) and during processing and end-use (replacement) of these products, where public exposure may also occur. The major route of exposure is inhalation. Air monitoring data were provided by two producers of chrysotile products. Data for the period 1992 to 1997, indicated that more than 80% of personal samples were less than 0.1 f/mL. Only 2 samples during this period exceeded 0.5 f/mL. Monitoring data (1991-96) at the second site where raw chrysotile is handled, indicated that approximately 60% of the personal air samples were less than 0.1 f/mL, with only one sample exceeding 0.5 f/mL. Personal and static samples for the years 1989, 1991, 1993 and 1995 at another site, where production of gaskets takes place were all less than 0.05 f/mL (static exposures below 0.01 f/mL). Air monitoring data from other sources were also assessed, which included an automotive aftermarket survey of service garages in Western Australia where exposure levels were found to be less than 0.1 f/mL. The NICNAS Automotive Aftermarket Survey showed that exposure to friable asbestos is highest in the brake bonding industry during grinding of brake shoes and cutting of brake linings. Work in the brake bonding industry is declining due to the availability of brake pad and clutch kits (preformed to standard sizes) which do not require modification before installation. However it was reported that 90% of current activities in this industry sector involve asbestos-containing material.
The main exposure to Australian workers arises from manufacture, processing and removal of friction products and gaskets. Home mechanics are also exposed during 'do-it-yourself' replacement of brake pads/shoes. Despite the introduction of non-asbestos parts for the new vehicle fleet, import data indicated that the import of chrysotile products (mainly friction products and gaskets) was not decreasing. The assessment determined that best practice must be implemented to minimise occupational and public exposure, and to minimise environmental impact, over the remaining period(s) of use. A risk reduction strategy using all available and appropriate measures is required to ensure that the risks posed by chrysotile are continually reduced and eliminated wherever possible.
General Public: The major source of public exposure is from chrysotile dusts generated by vehicle braking, although the level of exposure is very low. Overseas and Australian studies showed air levels of chrysotile fibres at busy intersections (less than 0.01 f/mL) or freeway exits (0.5 particles/mL), generated by braking vehicles. At a location of 30 metres from the nearest traffic, air levels were below the limit of detection. There are no data on exposure of home mechanics during the changing of brake pads and shoes. However, the time-weighted exposure of home mechanics is unlikely to be higher than that of workers in automotive brake service centres.
Environmental exposure assessment
When chrysotile is encapsulated in end use products such as brake linings and epoxy-resin adhesives, it is unlikely that fibres will be in a form where an environmental hazard is posed. Based on available data for Australia, it can be predicted that the manner of use of chrysotile (including release from driving and wastes from manufacturing) will result in a low exposure and hazard to the environment.
(c) Key data reviews consulted and a brief description
Key data reviews and national studies consulted are listed in the report that can be accessed at (http://www.nicnas.gov.au/publications/CAR/PEC/PEC9/20031215-pec9c.pdf ) and these were:
Australia Bureau of Statistics (1995) Motor vehicle census Australia. Canberra, Australian Government Publishing Service.
Australian Bureau of Statistics (1997) Motor vehicles in Australia. Canberra, Australian Government Publishing Service.
EC (1997) European Commission DGIII, Environmental Resources Management. Recent assessments of the hazards and risks posed by asbestos and substitute fibres, and recent regulation of fibres worldwide. Oxford.
ECETOC (1996) Toxicology of man-made organic fibres. Technical report no. 69. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium.
Federal Chamber of Automotive Industries (March 1997) VFACTS national vehicle retail sales report . FCAI, Melbourne.
Ferguson DA, Berry G, Jelihovsky T et al (1987) The Australian Mesothelioma Surveillance Program (1979-1985). Medical Journal of Australia. 147: 166-172.
Hughes RJ (1977) Asbestos in Australia - its occurrence and resources. Australian Mineral Industry Quarterly, 30(3): 119-127.
IARC (1987) IARC monographs on the evaluation of carcinogenic risks to humans: overall evaluations of carcinogenicity: an updating of IARC monographs volumes 1 to 42 (Supplement 7), International Agency for Research on Cancer, Lyon.
IARC (1988) Man-made mineral fibres and radon. IARC monographs on the evaluation of carcinogenic risks to humans :Vol 43. International Agency for Research on Cancer, Lyon.
IARC (1997) Silica, Some Silicates, Coal Dust and para - Aramid Fibrils. IARC monographs on the evaluation of carcinogenic risks to humans: Vol 68. International Agency for Research and Cancer, Lyon.
ILO (1989) Safety in the use of mineral and synthetic fibres: working document and report of the meeting of experts on safety in the use of mineral and synthetic fibres, Geneva, 17-25 April 1989. International Labour Organisation, Geneva.
IPCS (1986) Environmental Health Criteria 53: Asbestos and other natural mineral fibres. World Health Organisation, Geneva.
IPCS (1993) Environmental Health Criteria 151: Selected synthetic organic fibres. World Health Organisation, Geneva.
IPCS (1996) Health effects of interactions arising from tobacco use and exposure to chemical, physical or biological agents, Draft Monograph. World Health Organisation, Geneva.
IPCS (1998) Environmental Health Criteria 203: Chrysotile Asbestos. World Health Organisation, Geneva.
Leigh J, Hendrie L & Berry D (1998) The incidence of mesothelioma in Australia 1993 to 1995: Australian Mesothelioma Register Report, 1998. National Occupational Health and Safety Commission, Sydney.
Leigh J, Hull B & Davidson P (1997) Malignant mesothelioma in Australia (1945-1995). Annals of Occupational Hygiene, 41(Supplement 1).
Newstead SV, Cameron MH & Le CM (1998) Vehicle crashworthiness ratings and crashworthiness by year of vehicle manufacture: Victoria and NSW crashes during 1987-96, Monash University Accident Research Centre, Report No. 128, [http://www.general.monash.edu.au/muarc/rptsum/es128.htm], 14/8/98.
Rogers AJ & Leigh J (1991) Chrysotile and mesothelioma: information paper 6, 26th meeting NOHSC, 4 December 1991.
Rogers AJ, Leigh J, Berry G et al. (1991) Relationship between lung asbestos fibre type and concentration and relative risk of mesothelioma: a case control study. Cancer 67(7):1912-1921.
Rogers AJ, Leigh J, Berry G et al. (1994) Dose-response relationship between airborne and lung asbestos fibre type, length and concentration, and the relative risk of mesothelioma. Ann Occ Hyg, 38, Supplement 1: 631-638.
Rogers AJ, Yeung P, Johnson A et al (1997) Trends in occupational groups and industries associated with Australian mesothelioma cases 1979-1995. Ann Occ Hyg, 41, Supplement 1: 123-128.
Rogers AJ, Baker M & Conaty J (1997) Asbestiform minerals: worker exposure and risk assessment in some contaminated Australian mines. Appl Occup Environ Hyg, 12 (12): 867-871.
Rogers A & Leigh J (1993) Lung cancer risk from exposure to chrysotile (white asbestos) in Australia, NOHSC Meeting Agenda Item 23, March 1993.
III. Risk reduction and relevance to other states
(a) Estimates of the quantity of chemicals used, or imported/exported at the time of the regulatory action and, if possible information on ongoing trade
The quantities of chrysotile imported into Australia currently are unknown. The amounts of chrysotile imported into Australia was approximately 1500 tonnes per year from 1990 to 1999. However with the severe restriction effective from 31 December 2003, the importation amounts are likely to be very small. The regulatory action was based on the findings of the assessment report.
(b) Relevance to other States, i.e. those with similar conditions of use
Many other States already have restrictions on the use of chrysotile. For example at the time of publication of the NICNAS assessment report , Austria, Denmark, France, Germany, Italy, Netherlands, Norway, Sweden, Switzerland, United Kingdom and the United States were all noted to have legislated some form of restriction (see Appendix 7, page 165 http://www.nicnas.gov.au/publications/CAR/PEC/PEC9/20031215-pec9c.pdf ).
(c) Comments on the typical use of the chemical within the notifying country, with comments on possible misuse (if appropriate)
In Australia imports of raw chrysotile were used mainly in the manufacture of friction materials and compressed asbestos fibre (CAF) sheeting for gasket production with a small quantity being used in the manufacture of a 'non-sag' additive in an epoxy resin adhesive. All these uses, according to manufacturers, were being phased out. Brake linings and gaskets were found to be the main asbestos products imported for use in Australia, although most such products imported into Australia are asbestos-free.
Annex II
Supporting documentation for Australia's notification of chrysotile asbestos as a severely restricted chemical
1. Risk or hazard evaluation referenced in Section 2.3 of the notification form
http://www.nicnas.gov.au/publications/CAR/PEC/PEC9/PEC9index.asp
(link to PEC report - referenced in notification)
2. Relevant documentation for Section 2.4.1 referring to protecting human health
http://www.nohsc.gov.au/PDF/Statistics/Meso2003.pdf
(link to Mesothelioma 15th Report - referenced in notification)
http://www.nohsc.gov.au/PDF/Drafts/chrysotile-pdp-mar-01.pdf
(link to NOHSC public discussion paper - proposed prohibition on the use of Chrysotile Asbestos in Australia
http://www.nohsc.gov.au/PDF/Standards/Schedule2ReportPublicComment.pdf
Proposed Prohibition on Uses of Chrysotile Asbestos - Report of Outcomes of the Public Comment Process July 2001
(read in conjunction with the NOHSC March 01 public discussion paper)
http://www.nohsc.gov.au/PDF/Drafts/natlist-chrysotile-28jJune02.pdf
NOHSC public comment paper - Proposed National List of Exemptions to the Prohibition on the Workplace Use of Chrysotile
http://www.nohsc.gov.au/OHSLegalObligations/HazSubstancesAndDngGoods/ListofExemptions.doc
National List of Exemptions from the Chrysotile Prohibition 2003
(approved list of exemptions)
Prohibition of Asbestos Amendments 2001 - Amendment to Schedule 2 of the National Model Regulations for the Control of Workplace Hazardous Substances http://www.nohsc.gov.au/OHSInformation/NOHSCPublications/fulltext/docs/h4/377.htm
Other information
http://www.cdc.gov/niosh/ipcsneng/neng0014.html
(link to ICSC for Chrysotile - not referenced in notification although attached to notification sent)
The use of asbestos was severely restricted in Australia on 31 December 2003. The following documents were developed for the implementation of the regulatory activity.
Chrysotile Asbestos: Technical Assessment of Alternatives March 2001 http://www.nohsc.gov.au/pdf/Drafts/chrysotile-ta-mar-01.pdf
Chrysotile Asbestos: Health Assessment of Alternatives March 2001 http://www.nohsc.gov.au/pdf/drafts/chrysotile-ha-mar-01.pdf