Mesothelioma Applied Research Foundation Third Annual International Symposium on Malignant Mesothelioma
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The following is a summary of the presentations from the third annual International Symposium on Malignant Mesothelioma, held by the Mesothelioma Applied Research Foundation (MARF), in Chicago, Illinois on October 20 - 21, 2006.
Dr. Michael Harbut is the Director for the National Center for Vermiculite and Asbestos Cancers at Karmanos Cancer Institute at Wayne State University in Detroit, Michigan. What is Asbestos? The term "asbestos" was a word created for political and commercial ends and should technically encompass all of the six different types of fiber that look and act exactly like one another, that is, like asbestos. These fibers are resistant to degradation by water, heat, and flame and are flexible yet strong-making it the ideal building product. Who is Affected by Asbestos? People at high risk for developing mesothelioma because of exposure to asbestos are miners (including those who worked around fibers not technically considered asbestos), factory workers who use asbestos, automotive repairmen who work on brakes, construction and demolition crews, plumbers and pipefitters, and maintenance workers. Dr. Harbut points out others at risk who are not traditionally considered, such as do-it-yourselfers, those exposed unknowingly through the environment, and children who get hugged at the end of day by exposed parents. Once fibers have been inhaled, the cancer starts to form immediately, but many people have extended latency. Pleural cancer occurs 10-20 years after the first exposure, asbestosis 15-30 years later, lung cancer 20-30 years, and mesothelioma generally appears 30-40 years after exposure. There are cases of very young people who develop mesothelioma but doctors seemingly have no explanation for this. Where is Asbestos? Worldwide consumption of asbestos probably peaked around 1978 at approximately over 45,000,000 metric tons per year and has steadily been decreasing since, at approximately just below 20,000,000 metric tons at the turn of the millennium. But this is a conservative estimate as much data is not recorded. And while many areas in the United States are known sites of asbestos exposure and mining, Dr. Harbut wonders about the many other areas around the United States where asbestos contaminated products have been shipped. For example, vermiculite is an insulating material used in the attics of approximately 30 million homes across the nation. Vermiculite was mined in Libby, Montana and is significantly contaminated with tremolite and "therefore a new source of asbestos-related diseases." In essence, one should not be as concerned for the workers who continue to use better safety precautions, but worry about the houses where asbestos contaminated products have been shipped. Future of Asbestos-Related Disease Dr. Harbut suggests that because asbestos products are on the decline and banned in many parts of the world (not in the United States where only new products are banned from asbestos use), that the annual number of asbestos deaths will rise until approximately 2018 where it might plateau for a few years and then begin a slow decline. This brings some hope for the future, but leaves one questioning about the approximately 42,000 - 50,000 people who will be newly diagnosed before 2018.
Dr. Nick de Klerk is an adjunct professor at the School of Population Health at the University of Western Australia in Crawley, Western Australia. A 1980s study showed the high incidence rate of mesothelioma around the world. Since 1993, the mortality rates of mesothelioma have decreased significantly in Australia and throughout Europe, but this significant drop is skewed in part to the lack of funding for the mesothelioma foundation database where doctors recorded the number of mesothelioma patients treated. Since the 1990s, fewer cases have been reported but this does not necessarily mean that fewer cases have been diagnosed. (The cancer incidence data for Australia is available at www.aihw.gov.au/cancer/datacubes/index.cfm). Dr. de Klerk investigates the use of blue asbestos or crocidolite in Western Australia. The Wittenoom Gorge was the center for the blue asbestos industry from the 1940s-1960s and resulted in a large number of asbestos-related diseases and ultimately deaths throughout the region. Crocidolite was used prolifically throughout the area, piling up in the backyards of area residents throughout the desert region. It was also used in cigarettes as well. In the industry, de Klerk notes that workers generally ignored proper hygiene rules. Miners worked shirtless and often without the use of respirators or masks. James Hardy, Ltd. moved offshore of Australia to avoid compensation owed to victims of the blue asbestos it manufactured. This Australian epidemic is ultimately quite similar to W.R. Grace's industrial project centered in Libby, Montana.
Dr. Rabab Gaafar is an oncologist at the National Cancer Institute at Cairo University in Cairo, Egypt. The widespread use of asbestos continues in Egypt. Government regulations show the lack of consideration for workers' safety as they are directly exposed to asbestos and to area residents who are often also exposed. Dr. Gaafar shared pictures of factories containing asbestos products backed up directly to residential buildings as well as asbestos contaminated products lying outside factories. She suggests that more than 80% of residents in Egypt have been exposed. Asbestos continues to be used in Egypt because it is an excellent thermal insulator, moldable yet strong, and cost efficient. It is also used to embalm mummies. Most asbestos is now imported by Russia and Canada. Dr. Gaafar relayed the epidemic that asbestos is causing. Pleural mesothelioma cases are the most extensive in Egypt and surrounding countries while peritoneal mesothelioma is less extensive. Dr. Gaafar also discussed medical options for mesothelioma patients, giving suggestions of an aggressive treatment plan, especially for patients who do not respond to chemotherapy. Dr. Gaafar suggests a multimodal approach to treatment, as well-a combination of surgery, radiation, and chemotherapy.
Dr. Bruce Robinson is a physician in the Department of Respiratory Medicine at Sir Charles Gairdner Hospital in Perth, Australia and a past president of IMIG. Learn more about Dr. Robinson at www.brucerobinson.com.au. Dr. Robinson believes that asbestos-related diseases seem to come in waves, beginning first with the Wittenoom mine in Western Australia where blue asbestos (crocidolite) was used to prevent the red dust from the dry desert terrain from entering households. Consequently, the asbestos was everywhere and pictures from the era depict small children playing in mounds of it. Following this intense early wave, the next explosion of asbestos-related disease was found in the carpentering and plumbing industry and is currently a major concern. Dr. Robinson suspects the next wave will be the most shocking: incidental and unknown exposure. Asbestos fibers can be found everywhere now, lurking in the air we breathe, in our attic marketed to us under a different name, in our garage after falling from our brakes, and in the decomposition of older building materials. Dr. Robinson likened the ubiquity of asbestos to sunshine, "everyone's had a sunburn, but not melanoma, and everyone has asbestos fibers in their lungs but not mesothelioma." Because mesothelioma is an aggressive cancer, Dr. Robinson believes truly successful treatment will start with earlier detection and increased monitoring. Blood markers have been used to better detect and treat other types of cancer, and Dr. Robinson is hopeful that such an approach will be successful for mesothelioma. SMRP: A Potential Blood Marker in Meso Mesothelial cells have a molecule on their surface called mesothelin which "sticks" to the mesothelial cell and travels throughout the blood stream. The mesothelin molecule can be released in another form called "soluble mesothelin-related protein" or SMRP. Increased levels of SMRP appear to be a good early detector for mesothelioma as levels are not found to be as high in other cancers, even other asbestos-related cancers. Dr. Robinson's studies so far have determined that SMRP levels may be useful in first diagnosing a mesothelioma patient earlier and secondly to track disease progression. Additionally, patients with larger tumors exhibit higher levels of SMRP than do patients at earlier stages. SMRP may also be used to screen individuals exposed to asbestos to determine if they are at risk for developing mesothelioma. Dr. Robinson's lab has also studied several other potential blood markers but none have proven as reliable as SMRP. CA125 is another likely indicator but shows false positives for mesothelioma occasionally, thus it is not specifically associated with meso. Osteopoutin is also not as specific, and N/ERC occasionally shows false negatives making it not as sensitive a test for mesothelioma as SMRP levels. SMRP's Future For some of Dr. Robinson's patients, high levels of SMRP were detected five years before they were diagnosed with mesothelioma. Thus, even though SMRP appears to be a useful blood marker (and can even be detected in fluids, such as when fluid builds up in the lungs of mesothelioma patients), SMRP detection is still not perfect. Dr. Robinson hopes this test might be available for commercial use by early 2007. The FDA has granted its use at an orphan stage, and it is currently used for humanitarian purposes.
Dr. Brad Black is the chief medical director for CARD, an organization that provides health assessment, diagnosis, and treatment for asbestos-related diseases for individuals exposed to amphibole asbestos in Libby, Montana. Dr. Black's study in Libby, Montana mirrors Dr. Bruce Robinson's study in Western Australia. In both Montana and in Western Australia, two mining sites were known to cause high asbestos exposure for area residents. Through Dr. Black's CARD program, he is studying SMRP (soluble mesothelin-related protein) levels for individuals in Libby, Montana. (See also Diagnostic Markers - Bruce Robinson) Results of Dr. Black's study reinforce Dr. Robinson's findings-SMRP is elevated in patients with malignant mesothelioma and has also been detected at an increased level for ovarian cancer patients. In Dr. Black's study he is following two types of patients: those who have been exposed to asbestos but remain cancer-free and those who were exposed to asbestos but have developed mesothelioma. By comparing these two groups, Dr. Black will be able to establish what kind of a range of SMRP levels should exist in a population of people exposed to asbestos. This will ultimately serve to make the SMRP blood marker test a stronger, more reliable means of diagnosis for mesothelioma.
Dr. Anil Vachani is a pulmonologist at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania. Dr. Vachani's research focuses on early biomarkers for mesothelioma. In order to discover how to detect mesothelioma at an early stage, he is studying SCID mice (mice that have severe combined immune deficiency). Dr. Vachani first develops two new mesothelioma cell lines in Petri dishes. Then these epithelial mesothelioma cell lines are injected into the flanks of the mice. Tumors then grow at the site of the cell line injection and are allowed to grow to various sizes for up to several months. The tumors and the blood are then harvested from the mice at different stages for analysis. For example, some mice will only grow tumors for two weeks whereas others will grow tumors for four months. Once the tumor and blood are harvested, Dr. Vachani attempts to identify proteins that the tumor has shed into the mouse's blood. If Dr. Vachani can identify what proteins are being released, he may be able to find a biomarker for mesothelioma which may ensure patients receive treatment better suited to the state of their disease. Dr. Vachani's research is in its early stages and he hopes that his findings may be useful for patients with mesothelioma in the near future. However, Dr. Hans Schreiber, pathologist at the University of Chicago and founding member of the Academy of Cancer Immunology in Chicago, Illinois, raises concerns about Dr. Vachani's approach. Dr. Schreiber believes that the research is not cancer specific and that Dr. Vachani should instead be looking for mutations that occur in the mice instead of monitoring protein levels.
Dr. Sam Hammar is a renowned pathologist at the Diagnostic Specialties Laboratory in Bremerton, Washington. Mesothelioma produces a malignant tumor on the lining of three body cavities: the pleural lining (chest), peritoneal lining (abdomen), and pericardial lining (heart). Mesothelioma cases are relatively rare, 3,000 - 4,000 cases each year, compared to lung cancer which is diagnosed in approximately 180,000 people per year. Dr. Hammar attributes mesothelioma to two causal factors-asbestos exposure and therapeutic radiation. Common features of mesothelioma include dypsnea (shortness of breath), pleural effusion (accumulation of fluid in the chest cavity), and chest pain. What Dr. Hammar calls "B Symptoms" or lesser features, include fever, night sweats, malaise (a nonspecific feeling of discomfort), weight loss, and fatigue. Bremerton has the highest population of malignant mesothelioma patients in the United States. When a patient presents with mesothelioma symptoms and a pathology report reveals mesothelioma, the patient undergoes thorascopic surgery immediately, within one to two days. In other areas around the country, a patient may not undergo surgery for anywhere from a few months to a year even if they have known asbestos exposure. Dr. Hammar notes the most common type of mesothelioma is pleural, affecting 90% of patients and peritoneal affecting 10%. From personal experience, Dr. Hammar finds a latency period for a pleural effusion to occur anywhere from 3 - 20 years after asbestos exposure and a 25 - 72 year latency period for malignant mesothelioma. Plaques and nodules are good indicators of mesothelioma at an early stage and should be treated immediately. Another type of mesothelioma is known as pseudo mesothelioma, a type of cancer that looks like mesothelioma but in actuality is much worse. There are four different types of pseudo mesothelioma known, with approximately 20 subtypes. Dr. Sam Hammar has generously offered to review pathology reports for a second opinion.
Dr. Raja Flores is a thoracic surgeon from Memorial Sloan-Kettering Cancer Center in New York. Dr. Flores's presentation on radiological imaging captured exactly what X-rays are used for and what types of imaging are good detectors of mesothelioma. X-rays help doctors find out "what's happening in the body" and they provide an idea of the disease progression in the chest. Once the state of the disease is understood, a course of treatment can be decided upon. For example, if the disease is minimal, surgery may be the best treatment, but if it is extensive, radiation may be more appropriate. A patient's course of treatment is determined by the stage of the disease. Stage I patients tend to have a three - five year prognosis while Stage IV patients may have one year on average. An X-ray also may determine where the tumor is headed. If it appears to be spreading towards the belly, surgery may not be the best option and instead chemotherapy may help control the progression. Thus X-rays may redirect a doctor's treatment plan. Additionally, patients may need more than a CAT scan (also called a CT scan) to detect activity. When a tumor is growing in the parietal pleura (the outer lining attached to the chest wall), a CAT scan may not be able to show the depth and range of the disease. However a CAT scan is the cheapest and single most informative method of detecting disease progression. A CAT scan with contrast is better because it can reveal lymph node involvement. A PET scan detects the metabolic state of the disease, showing the physiology and cell division occurring. It is also useful to detect the spread of the disease into the mediastinum and into fissures in the lung. This evaluation is important for surgeons because when the tumor advances into these areas, it is difficult to perform a pleurectomy with decortication because it may cause bleeding. An MRI gives a detailed picture of the body but may not always be helpful. In a group of Dr. Flores' patients who were evaluated with an MRI and then determined that surgery was the best treatment, once in surgery, 34% were found not to have a tumor. Dr. Flores remarked that no surgeon wants to open his patient and find that nothing should be done, "it is better to save the patient from surgery" if possible.
Dr. Helen Clayson is the Medical Director at St. Mary's Hospice in Cumbria, United Kingdom. Mary Hesdorffer is a clinical research nurse at Herbert Irving Comprehensive Cancer Center at Columbia University in New York. Together, Clayson and Hesdorffer had several suggestions to help ease disease management. Dr. Clayson first addressed some of the hang ups of asbestos-related disease in workers in the traditional industries, such as miners, naval boiler tenders, and railroad workers. To begin with, for many such workers, their job is a source of pride but when the job causes a terminal illness, it presents a problem. Many people remain stoic about their exposure because to complain about their disease is to complain about their job which in turn, can be almost unpatriotic. So, much of the hang up on their disease can be a perception. Breathlessness This perception can also manifest physically. Dr. Clayson suggests that breathlessness is caused by fluid build up in the chest, but it is also a mental perception. She suggests that breathlessness interferes with daily life and can cause an identity crisis for some patients. For example, someone known to be the epitome of health who suddenly has problems breathing after the smallest activity may have a difficult time adjusting to a new lifestyle. Breathlessness is terrifying, but is mostly caused by muscle deconditioning and attributable to anxiety. It is a terrible cycle because as the disease progresses, exercise is more difficult, and without exercise to help strengthen the muscles, the situation escalates. What you can do:
Pain Pain is another symptom of mesothelioma and can be quite uncomfortable due to tumor growth, muscle deconditioning, and nerves affected by the disease. Pain caused by abdominal ascites can be alleviated by a doctor who inserts a tube in the abdomen that limits fluid accumulation. However this can also cause edema (swelling) in other parts of the body. A thoracentesis can also alleviate any pain associated with fluid buildup. Sometimes pain can be difficult to control if it is complex, that is if it not just attributable to fluid build up or pressure from a tumor. Pain can have multiple causes and require a variety of treatments. It is important to associate pain correctly, for example, people who get nauseas after receiving chemotherapy may not have an adverse reaction to chemotherapy, but may be having an adverse reaction to anesthesia or pain medication, not the chemotherapy. Treat symptoms accordingly. Clayson and Hesdorffer suggest not letting pain go unnoticed or untreated. Mesothelioma is a terrible disease and seeking appropriate relief is always advisable instead of stoically allowing the body to be uncomfortable. Chemotherapy Some side effects for chemotherapy include a loss of appetite and some people can actually become anorexic when they associate eating with a bad outcome. The best thing to do in this case is to eat small, frequent meals or snacks. That way, you won't associate a feeling of fullness with discomfort. Eat new foods and foods high in protein. Start with eggs or cream cheese but avoid oatmeal which does not contain much protein and only serves to fill you up. If you don't feel hungry at all, sometimes a light exercise can stimulate your body and make you hungry. If you are hungry, eat what sounds good to you. Don't worry about the heart healthy diet; eat whatever you want, whenever you want - cheesecake, milkshakes with protein, or soul food. The main purpose of eating is to intake calories, do this in whatever way you can. If you're still having problems with eating, if it seems like a job, pamper yourself. Set a nice table and light candles. Do something to take the negativity of eating away. Other side effects of chemotherapy may include a skin rash which can be treated with benadryl or an aveeno oatmeal bath that can sooth skin irritation. Chemotherapy can also cause dehydration which in turn causes diarrhea and stomatitis (inflammation of the mouth or canker sores). Be sure to always drink plenty of liquids or eat soft foods. Sucking on ice chips may help mouth inflammation. Stay away from spicy foods and eat cold items. The overall message is to be aggressive in treating side effects. It may require a variety of specialists, but patients are well entitled to proper relief.
- Raffit Hassan, Paul Sugarbaker, John Chabot, and Robert Taub Dr. Raffit Hassan is an investigator at the Mesothelin-Expressing Cancer Unit of the National Cancer Institute based in Bethesda, Maryland. PART I: Chemotherapy Dr. Hassan spoke about chemotherapy use as one part of a multi-modal management to peritoneal mesothelioma. The first line of treatment is currently a combination of Pemetrexed (ALIMTA) with either Cisplatin or Carboplatin. Carboplatin is similar to Cisplatin but is a weaker form and administered as a substitute when a patient has adverse reactions to a stronger Cisplatin prescription. Dr. Hassan is currently investigating two drugs that combat mesothelin (a protein that adheres to the outer layer of mesothelial cells and allows the cancerous cells to progress). Both drugs, known as SSIP and MORAB-009, are still under clinical trial but appear promising. One patient survived five years with mesothelioma only receiving SSIP. MORAB-009 appears to prevent mesothelioma from spreading by inhibiting mesothelin from binding to mesothelial cells. PART II: Staging for Surgery Dr. Paul Sugarbaker is the Director of Surgical Oncology at the Washington Cancer Institute of the Washington Hospital Center in Washington, D.C. Dr. Sugarbaker is currently creating a staging system for mesothelioma patients. Such a system divides mesothelioma patients into the appropriate stage of cancer progression and will allow doctors to better treat patients by understanding clearly how far the cancer has progressed. A unified staging system does not yet exist for peritoneal mesothelioma patients, but Dr. Sugarbaker is attempting to divide patients into two major categories: first those patients who would benefit from aggressive treatment and then those patients whose cancer is beyond treatment. Creating a staging system includes establishing an eligibility criteria and a uniform management plan. Before treatment is decided, uniform tests should be done, such as a CAT scan of the chest, abdomen, and pelvis within two weeks preoperatively. Pathology will be reviewed appropriately as well as all prior clinical information. In all, 26 parameters would be analyzed based on three conditions: clinical, radiological, and histopathological (a study of the affected tissue). By clearly grouping patients into categories, Dr. Sugarbaker hopes to better understand why some patients improve with treatment while others do not benefit. PART III: Adjuvant Therapy Post-Surgery Dr. John Chabot is a surgical oncologist at Columbia University Medical School in New York. Dr. Chabot's research focuses on treatment for peritoneal mesothelioma after surgery. Specifically, Dr. Chabot has studied the effects of adjuvant and neoadjuvant therapy. Adjuvant therapy is similar to a catalyst treatment that helps prevent the body from having a relapse after the cancer has been debulked or largely removed. Dr. Chabot is working with very new adjuvant treatments, referring to them as "NeoNeoAdjuvants." This type of immunotherapy has been successful following a laparotomy surgery especially for peritoneal mesothelioma patients at Stage I and II. The median survival for these patients was approximately three years and appears applicable to the general population. PART IV: Multi-Modality in Summary Dr. Robert Taub is a medical oncologist directing the Connective Tissue Oncology Program at the Herbert Irving Comprehensive Cancer Center at Columbia University College of Physicians and Surgeons in New York. Dr. Taub highly recommends a trimodal therapy and reports that patients who have received this treatment are doing much better. While many mesothelioma specialists differ on the order of some multi modal treatment and what type of treatment a patient should receive, Dr. Taub reports that most doctors have reached some agreement. For example, the tumor should be surgically reduced, but this could be done using different avenues. Intraperitoneal chemotherapy is beneficial, and Dr. Taub recommends that effective chemotherapy should be given, like Alimta. Dr. Taub also discussed heated intraperitoneal chemotherapy. Benefits are yet unknown about this, but it is more toxic. In the long run, this could either be a benefit or a detriment, but results are not yet firmly established. Dr. Taub acknowledges that doctors may differ on some viewpoints such as the need to initially resect the tumor, having a "second look" surgery where a patient has two surgeries for the same tumor, and the need for whole abdominal radiation. Much research is still being done on peritoneal mesothelioma. Dr. Taub will attend a conference in Milan in December 2006 with the aim to reach a consensus about treating peritoneal mesothelioma.
Dr. Raja Flores is a thoracic surgeon from Memorial Sloan-Kettering Cancer Center in New York. Dr. Harvey Pass is Chief of Thoracic Surgery and Oncology at NYU School of Medicine and Comprehensive Cancer Center in New York and is Chairman of the Science Advisory Board of the Mesothelioma Applied Research Foundation (MARF). Approximately 3,000 new cases of mesothelioma occur each year. Most are epitheliod mesothelioma of which the majority affected are men. Mesothelioma in essence freezes muscles in the diaphragm and lung resulting in a sort of frozen chest. The pleural lining fixes to the lung, trapping it. What occurs afterwards are diseases like pneumonia, infections, and sepsis (an infection caused by bacteria in the blood) which can ultimately be fatal. Proper Diagnosis A proper diagnosis should be obtained before seeking treatment. A thoracentesis to remove any fluid build up in the lung is a telling diagnosis, but Dr. Flores suggests that a VATS (Video Assisted Thoracic Surgery) is the most accurate diagnosis. Once diagnosed, sarcomatoid mesothelioma patients tend to have a poorer prognosis (as opposed to epitheliod mesothelioma). Under a microscope, it is not always easy to differentiate between some of the mesothelioma types, but histological staining provides more accurate diagnosis. Dr. Flores suggests that it is important to monitor the cancer for approximately one week before performing surgery to ensure proper treatment is being given. Dr. Flores brings up the purpose of surgery, questioning whether it is getting rid of the tumor or getting rid of the diseased lung that can later cause a fatal infection. Understanding the purpose of a surgery is key to choosing a treatment plan. Regarding the historical treatment and outlook prognosis given to mesothelioma patients, Dr. Flores helps clear a few misconceptions. To begin with, Dr. Flores acknowledges that diagnosis and treatment options have improved significantly. Older data for mesothelioma patients is "contaminated" with patients improperly diagnosed with meso. Also, because a proper staging system is still being developed, all mesothelioma patients have been lumped in together. The reality is that all cancer patients should be considered at the appropriate stage of their disease so stage III patients were lumped in with stage I patients and there is "no wonder why everyone was told they had a poor prognosis." Because proper stage tracking was not occurring, all patients were given the same dismal outlook. Treatment Options With proper staging, patients have better tailored treatment options, including the type of surgery they can receive. Dr. Flores does not suggest that any patient merely opt for observation of the cancer. A talc pleurodesis (where a chemical agent is put into the lungs to prevent fluid accumulation) can be a good palliative treatment to ease breathing. On the other hand, he refers to another surgery known as palliative pleurectomy as a "bail out procedure." In his opinion the doctor cannot move the tumor and a lot of gross tumor is left inside, making the surgery an unnecessary burden on the patient with little benefit. More invasive surgeries include the Pleurectomy with Decortication (P/D) and an extra pleural pneumonectomy (EPP). In a P/D the surgeon debulks the tumor from the lung as best able but leaves the lung healthier and intact. A P/D is intended to cure a patient of mesothelioma and sparing the lung is a huge benefit. An EPP is also intended to cure the patient but is more radical because this surgery requires the lung to be removed. Much controversy exists between these two procedures. Dr. Flores believes that the EPP is theoretically more attractive because it keeps the entire tumor together in a pleural envelope and the tumor does not spread as easily to other areas. He also agrees that the EPP is an easier surgery to perform. Dr. Pass acknowledges though, that surgery should perform the greatest good for the patient, and says surgeons should always keep this in mind. Dr. Pass reiterates one of the significant problems of choosing between these surgeries-no statistical data exists between the long term benefits of an EPP verse a P/D. Doctors continue to get better at performing both types of surgery. Patients at a stage I tend to do much better with an EPP, with an average survival rate of approximately 30 months whereas patients at stage IV have an average survival of eight months. The Pass Corollary Recently, Dr. Pass has been performing more P/Ds than in the past. When deciding between surgeries, he first has to ensure that the patient can tolerate the surgery. He echoed the Pass Corollary, "You're only as good as what you do for the patient." Thus, Dr. Pass measures the disease progression before and after surgery and is always mindful of tailoring surgery to the patient. Both Dr. Pass and Dr. Flores agree that half of the battle occurs before a patient enters the operating room. A PET scan is recommended to detect exactly where the tumor is and to ensure that no disease exists outside of the chest. Only those patients with a contained tumor should elect surgery in the first place. Some criteria about surgical options entail placing the patient at the appropriate stage. For example, stage I patients have normal fluid, minimal bulk, and the lung still expands well. Sometimes, the doctor must reassess a treatment plan once inside if the disease stage is unclear before undergoing surgery. However the doctor is obligated to tell a patient that a P/D is not recommended even if the patient is stage I if the tumor is in bulk. For some patients, taking the whole lung is not advisable, but the doctor should be reasonable about when to take the lung or not. For patients at stage II, a P/D can be more difficult but a good surgeon has patience and knows what the endpoint should be. Heavy smokers should not have an EPP because they need both lungs. Those patients who have an EPP may not do better in the long run because they are surviving on only one lung. Taken holistically, patients who receive a P/D tend to do better than those who undergo an EPP. But both do well at an early stage, and females tend to recover from surgery better than men. Patients Bear the Burden The bottom line is that surgeons need to be flexible in their operations and therapies need to be improved as well. Educating "front line" doctors also needs to be addressed and is a huge concern for mesothelioma patients as many are misdiagnosed for several months. This education in medical offices is slowly happening due to news media and research. Unfortunately much of the burden falls on the patient to perform their own research and decide treatment options. Dr. Flores suggests patients continue to get a CT scan every six months, and Dr. Pass recommends every three months to monitor progression.
Dr. Jeremy Steele is a Consultant Medical Oncologist for Lung Cancer and Mesothelioma at St. Bartholomew's Hospital in London, England. To learn more about Dr. Steele's research, please visit www.mesothelioma.co.uk. Dr. Steele comments that he has seen a significant increase in mesothelioma patients, approximately 150 new patients each year. Dr. Steele suggests chemotherapy as an option for patients not seeking surgical treatment such as an extra pleural pneumonectomy (EPP) where the affected lung is removed entirely or a pleurectomy with decortication (P/D) where the tumor is debulked from the lung but the lung is left intact. Chemotherapy is advisable for fit and mobile patients who exhibit "disease activity," that is, they show symptoms such as weight loss or night sweats that suggest the cancer is active. For patients fitting this profile, Alimta combined with Cisplatin shows a slightly better survival rate that Cisplatin alone. Some side effects do occur but the real world view for this chemotherapy is that there is no hair loss in most patients and most side effects are usually tolerable. Some patients do not respond to Alimta and Cisplatin and others may show more progress in a second round. It is usually given moderately every two weeks. More serious side effects may include increased toxicity after extensive chemotherapy, neutropenia (a blood disorder occasionally caused by chemotherapy) or diarrhea. Dr. Steele does not advocate radiotherapy as he generally sees no significant reduction in the tumor. It serves mostly for palliative purposes to relieve pain. Asymptomatic patients may choose close observation and follow-ups with their doctors before beginning chemotherapy. But Dr. Steele reminds that close observation means just that. Do not allow for extended periods of time to pass without checking in and keeping track of disease progression. This should be an active watch-and-wait approach.
Dr. Sjaak Bergers works closely with Dr. Paul Baas in the Netherlands. Their team has received funding from the Mesothelioma Applied Research Foundation (MARF). This research team is currently studying the effects of thalidomide for mesothelioma patients. Thalidomide was initially sold to pregnant women in the late 1950s and early 1960s to alleviate morning sickness and allow them to sleep easier. However, women who took thalidomide gave birth to children with severe abnormalities. What actually happened was thalidomide prevented blood vessels from growing. Now it is currently being investigated as a treatment option for mesothelioma patients to prevent the cancer from growing by inhibiting blood vessels. This treatment is currently in its first round of investigations and is not known if it will be a beneficial treatment for mesothelioma patients. Treatment results for the 110 males given thalidomide are not yet available. Australian males may soon be joining the clinical trial.
Dr. Daniel Sterman is Director of Interventional Pulmonology and Clinical Director of Thoracic Oncology Gene Therapy Program at the University of Pennsylvania Medical Center in Philadelphia, Pennsylvania. To better understand the treatment results of a clinical trial, Dr. Sterman first clarified what a clinical trial entails. Clinical trials are designed as a way to develop new drugs that are safe and effective. The FDA has a stringent process that clinical trials must meet before trials are deemed safe for humans. The first stage is actually a pre-clinical trial where a drug is developed and tested in the laboratory and in animals to prove the drug is safe and effective. However, because animals do not always respond the same way humans respond to drugs, this process can take years before the FDA allows a drug to be used in an actual clinical trial with humans. The FDA evaluates clinical trials at each stage to determine the next steps in a trial and establish end points for future trials. Once the trial has successfully undergone the FDA's vetting process, it will be approved to begin phase I testing. Phase I A phase I clinical trial must determine if the drug in question is safe for humans. This is the first time the drug has been used in humans and usually only 20-80 healthy volunteers are tested, generally in low doses of the treatment for approximately six months to one year. Doctors attempt to determine how much of the drug is appropriate, how often it should be given, and what the side effects are. However, the primary goal of a phase I clinical trial is to do no harm to the participants. For example in Wisconsin, the Mesothelioma Gene Therapy Schema phase I clinical trial's goals were first to determine the safety and toxicity of the treatment. Then, to determine the maximum tolerated dose of the treatment. Also, documenting the gene transfer results was one of the primary goals. However, documenting the immune responses and the tumor responses to the treatment is not a primary end goal of a phase I clinical trial, even though this data is gathered. Primary goals concern safety.
Phase II A phase II clinical trial is designed to determine safety and efficacy. These trials generally include more patients than phase I, approximately 40-400 patients. At phase II, the study's purpose is to test the therapeutic effect of the treatment and gather patient responses. For example, the phase II trial for interleukin II was done in France. Results were gathered after administering treatment into the blood stream and into the chest. This clinical trial was designed to prove more than safety; it was also designed to show how effective the treatment is. However, this trial has not been done as a phase III trial, yet.
Phase III A phase III clinical trial is designed to prove controlled safety and efficacy in a larger population. At this point, several hundred to approximately 3,000 patients may be included for testing. The primary goal of a phase III clinical trial is to determine if the drug is worth using. For example, the chemotherapy drug Alimta was tested in a phase III clinical trial to determine if it worked better than Cisplatin. Patients were elected randomly to receive treatment and their response rates were tested. Once testing is complete, the sponsor submits an application to the FDA for marketing approval. The FDA has at least six months to review a "priority" application for drugs for a life-threatening need and ten months for a standard application. However, the FDA's ultimate approval may take up to two years. Even after the FDA approves the treatment, the sponsor may continue to monitor treatment in order to evaluate long-term results or the results of a treatment's use in combination with another therapy. To learn about the results of clinical trials, Dr. Sterman suggests accessing www.clincialtrials.gov, www.centerwatch.com, the NCI website at www.cancer.gov/clinicaltrials, or also through IMIG (www.imig.org) or MARF (www.marf.org). For those patients who wish to be included in a clinical trial, Dr. Nicholas Vogelzang, who is on the Board of Directors of the Mesothelioma Applied Research Foundation (MARF), suggests that getting access into one is relatively easy. Ask your doctor if s/he knows about any ongoing trials or get a reference to someone who might know. Dr. Vogelzang suggests that patients start at the end of phase I when the dosage level is approximately where it should be.
Dr. Sunil Sharma is Chief of the Section of Gastrointestinal Oncology and of early phase clinical programs for the Nevada Cancer Institute in Las Vegas, Nevada. Dr. Sharma studies epigenetics, turning a gene "on" or "off." He studies heritable changes in gene expression that occur without changing the DNA sequence. His research follows why some genes are "turned on" or "off" and may explain why sporadic mesothelioma forms, such as a genetic tendency or environmental factors. As cancer cells grow they can undergo a process called acetylation that effectively "silences" genes that might prevent the cancer from growing. New drugs have recently become available that can "reactivate" these genes and in turn kill the cancerous cells. These new drugs are known as Histone Deacetylase inhibitors (HDAIs) and include drugs such as vorinostat (recently approved by the FDA), LBH589, PXD101, and MS-275. Specialists do not know exactly how these HDAIs work. Some may cause cell death, increase sensitivity to chemotherapy, or cut off a cancer's blood supply, for example. Much of this research is in early stages and Dr. Sharma suggests that good clinical trials still need to be designed to test HDAI therapies.
Dr. Steven Albelda is Vice Chief and Director of Lung Research in the Pulmonary and Critical Care Division at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania. He works closely with Dr. Daniel Sterman (see also Accessing Cutting-Edge Treatment Through Clinical Trials). Gene therapy is essentially "the transfer of genetic blueprint material into cells." It was originally intended to treat inherited disorders such as hemophilia, but over the past decade has been most often used in treating cancer. In treating patients, suicide gene therapy appears promising. Doctors inject a gene that is normally non-toxic into tumor cells so that the cells would take in the treatment. Then the gene releases an enzyme killing tumor cells. Dr. Albelda's team believes mesothelioma patients are likely good candidates for gene therapy because the tumor is usually localized and metastasizes relatively late and doctors can gain easy access into the pleural space. During clinical trials, doctors inserted a chest tube into a patient's pleural space and instilled an adenovirus with Herpes Simplex Thymidine Kinase suicide Gene. Two days after the gene was instilled, doctors took a biopsy of the area to determine if the gene transfer was successful. Fourteen days after the biopsy, patients were given the prodrug ganiciclovir to treat the adenovirus. For the 34 patients, there were minimal, well-tolerated toxicities and a generally successful gene transfer. Patients who received higher doses showed more tumor regression. Two patients showed complete regression and have currently survived over seven years! Unfortunately, due to an unrelated clinical trial, all trials at the University of Pennsylvania were suspended. Still, Dr. Albelda and his team continued to speculate about the treatment, and believe that the treatment's success was due in part to immunological responses induced by the treatment. Since then, the team has attempted to create a direct response in the immune system. Using an adenovirus with interferon-beta, the team hopes to active the immune system. In preclinical trials, animals with tumors had a 100% survival rate with the interferon-beta treatment. The team has also received support from a company named Biogen (www.biogenidec.com) and clinical trials have been approved from the University of Pennsylvania, the Recombinant DNA Advisory Committee (RAC) division of the NIH, and the FDA. Clinical trials began in August 2003 with 10 patients who either had pleural effusions due to mesothelioma or metastatic disease. Patients were given the interferon-beta treatment through an intrapleural catheter and monitored as inpatients for 48 hours with follow-up pleural and blood sample over time. PET images showed a dramatic response in the third patient treated (a 47 year-old-woman with metastatic ovarian cancer) and several mesothelioma patients had disease stability for six months to a year and a half. Another trial is ongoing where patients receive two doses of the interferon-beta treatment two weeks apart. Only six patients have been treated and one has shown a response after two months. Future plans include a higher dose of the treatment and possibly combining the interferon-beta treatment with surgery or chemotherapy. Regardless, Dr. Albelda recognizes that gene therapy should be developed further to provide more efficient transfer techniques and to gain a better understanding of tumor biology. Research is ongoing.
Dr. Richard Kornbluth is associate adjunct professor of medicine in the Viral Malignancy Program at the University of California San Diego in La Jolla, California. Dr. Kornbluth is studying the immune response to tumors. Once a tumor has grown large enough to become a problem, it usually has effectively suppressed the immune system. Immune responses begin with dendritic cells which accumulate antigens from tumors and then activate killer lymphocytes to combat the tumor. However, tumor cells can make a substance that will "turn off" the dendritic cells and allow the tumor to grow. Dendritic cells can be reactivated through CD40 ligand (CD40L) which is a molecule made by CD4 helper T cells. CD40L can stimulate the dendritic cell and eradicate the tumor. Dr. Kornbluth's lab has created a new form of CD40L that stimulates immune responses better than natural CD40L. So far CD40L has only been tested in mice, but when injected it has cured some mice of tumors. However, in mice with mesothelioma tumors, it has not proven as effective. Another form of immunotherapy has shown substantial results in mice with mesothelioma tumors. A form of bacterial DNA called "CpG" is injected along with a "virus-like unnatural form of double-stranded RNA called 'poly(I:C)'." Dr. Kornbluth hopes that more research into immunotherapy will someday be useful for mesothelioma patients.
Dr. Bart Lambrecht is head of pulmonary research at Erasmus University in Rotterdam, The Netherlands. Dendritic cells help the body's immune system by releasing antigen cells to counteract disease; they specifically release lymphocytes. However, by the time a tumor has grown large enough for the body to recognize it as a disease, the tumor has usually released chemicals to stifle dendritic cells, rendering them useless against the tumor. Dr. Lambrecht has grown dendritic cells in vitro in a healthy environment and has studied their effects when injected into a "mature state" where a tumor is present. His team then studied the dendritic cells in a phase I clinical trial to determine the safety and toxicity of the treatment for mesothelioma patients. In preclinical trials, mice who received the dendritic cell treatment before tumor growth were protected for months from the tumor. Mice who received the treatment after tumor growth were able to slow the tumor's progression. In clinical trial patients who received the dendritic cell treatment showed minimal side effects, such as a small fever and mild local reactions. Treatment appears safe and feasible for mesothelioma patients; their immune responses to the treatment were measured through skin tests and blood analysis. Research is ongoing.
Chris Hahn is the executive director of the Mesothelioma Applied Research Foundation (MARF). He works tirelessly to bring about new legislation to protect asbestos victims. Mr. Hahn delivered the closing speech at the MARF Symposium in Chicago on October 21, 2006 with a message to mesothelioma patients: Believe in a Cure. He opened with a statement from Dr. Harvey Pass, MARF Science Advisory Board Chairman, "it is no longer acceptable to dismiss mesothelioma as untreatable, for 'untreatable' implies an acceptance of failure. We must dispel this attitude of nihilism." Indeed, as medical research improves, this skepticism is beginning to be broken, but much still needs to be done politically to ensure research and legislation will help mesothelioma patients. Each year approximately 3,000-4,000 people are diagnosed with mesothelioma and sources speculate where the peak for patients will fall. Some say that mesothelioma has been declining since the early 1990s, others suggest the peak came around the early part of this century. Needless to say, many more will be diagnosed in the upcoming years, perhaps another 100,000 over the next 50 years according to the American Journal of Epidemiology. Contributing factors include the attack on the Twin Towers and subsequent wreckage, vermiculite plants in Montana, Arizona, and Missouri where products were then shipped nationwide, and continued exposure to unknown victims like those who walk past a car with brake dust or the politicians who walk through the underground tunnels in Washington, DC insulated with asbestos. Cases of mesothelioma in the United States are relatively low compared with national exposure where some developing countries are increasing the use of asbestos. Unfortunately, there seems to remain a societal disregard for asbestos and mesothelioma. Politicians and big business don't want to talk about it the majority take an apathetic stance towards change. Mr. Hahn points out, that serious discussion about mesothelioma is unpopular socially, is unpatriotic (as approximately one third of patients were exposed while serving in the U.S. Navy), it counteracts our capitalist system which encourages businesses to make the most of profits, and it silences people out of fear and guilt. Consequently, mesothelioma continues to go un-discussed, unlegislated, and under funded. Big business wants to steer clear of litigation as well, as more cases are brought to trial. Their money would be better served in researching a cure than funding a defense, though. Even though the businesses that poisoned their workers don't want to do anything about it and the government seems slow to act, MARF is moving forward. The foundation is funding research, advocating at local and national levels, and providing support and education to mesothelioma victims. With their "organized passion," the MARF team has seen results. In 2005 over $2 million was raised to help accomplish their goals. And the nation is beginning to pay attention. The National Cancer Institute's involvement is increasing, congressional representatives are uniting, and local media is getting the word out. MARF hopes to bring about social change, moving from victimism to activism through volunteering, education, government interaction, litigation, and simply telling the story. MARF dares to have "Audacious Hope!" for the future of mesothelioma patients. *** November 1, 2006 *** |