COPD Chronic Obstructive Pulmonary Disease

A brief discussion of the diagnosis and management of COPD.

COPD Chronic Obstructive Pulmonary Disease

Lung Cancer

How do you know if you are at risk of developing lung cancer?
Many things are associated with an increased risk of developing lung cancer.

The National Cancer Institute expected nearly 215,000 people to be diagnosed with lung cancer in 2008, and nearly 162,000 people to die of lung cancer in 2008!

Smoking is the most common cause of lung cancer, and is the best established preventable risk factor for lung cancer (as well as bladder and other cancers). According to the National Cancer Institute, cigarette smoke contains over 4,000 chemical agents and at least 60 known carcinogens (cancer-causing agents)! Few of us would be willing to live or work in an environment that contains that many risky chemicals?!

Other risks include environmental exposures to known carcinogens. A few of them have received significant attention in the media.

Environmental tobacco smoke (aka "second hand smoke") is perhaps the most frequently encountered environmental risk factor known to cause lung cancer. The inhaled smoke is not filtered, and many environments are associated with highly concentrated second hand smoke (i.e., public restaurants, nightclubs, taverns, etc.).

The Environmental Protection Agency estimates that as many as 3,000 people die each year as a result of environmental tobacco smoke exposure. That is 10 times the number of Americans killed in armed conflict in Iraq in 2008, according to globalsecurity.org, and nearly the same number of people who died, directly or indirectly, as a result of the September 11, 2001 attacks on the World Trade Center (according to http://nymag.com/news/articles/wtc/1year/numbers.htm).

While not a common cause of lung cancer, asbestos causes mesothelioma, and has received a great deal of attention from the media, legal system, and Congress. In 1999 nearly 2500 people died in the United States from mesothelioma (Center for Disease Control, National Institute for Occupational Safety and Health). Plumbers, pipefitters and steamfitters are the occupations at greatest risk. For additional occupations associated with exposure to asbestos, please refer to the presentation "Malignant Pleural Mesothelioma". Smoking does not increase the likelihood of developing mesothelioma, however, smoking and exposure to asbestos increases your chance of developing other types of lung cancer by 50 fold!

The second most common cause of lung cancer is radon. According to the National Cancer Institute, it is thought that radon is responsible for as many as 15,000-22,000 deaths from lung cancer each year. Radon is a naturally occurring odorless gas created by the decay of uranium, found in many rocks and soils. Granite counter tops have recently been found to emit radon gas. While in low concentrations outdoors, it can reach concentrated levels indoors in basements and underground mines or shelters. There are radon detectors, like carbon monoxide detectors, that can alert people to dangerous levels of radon gas. Fortunately, the risk of dangerously high radon gas levels can be decreased by improving ventilation systems. For more information about radon gas, visit the Environmental Protection Agency.

What are symptoms concerning for lung cancer?
Symptoms of lung cancer can be nonspecific and can be similar to symptoms of other illnesses, such as congestive heart failure, pneumonia and pulmonary fibrosis. Symptoms of lung cancer can include: chest pain, unexplained weight loss, unexplained fever or chills, new or prolonged cough, bloody cough, new or worsened shortness of breath, decreased appetite. If you have any of these symptoms, you should see your doctor to discuss the possible causes.

What will your doctor do to determine if you have lung cancer?
First, your doctor will ask you questions relating to your past medical health, your family risk factors, and your current symptoms. Your doctor will also perform a thorough physical exam. He or she may also opt to order tests to further evaluate your symptoms, such as blood work, breathing function tests, chest x-rays, CT of the chest, PET scan, etc. Should there be any suspicious looking areas on your chest x-ray, CT of the chest, or PET scan, your doctor may refer you to a pulmonologist (lung doctor) or a cardiothoracic surgeon.

A pulmonologist, a doctor specializing in problems and diseases affecting breathing, will listen to your medical history, perform a physical exam, order tests, and possibly perform a bronchoscopy to obtain tissue samples of your lungs to look for cancer or other causes of apparent lung masses. Bronchoscopy is a means of looking inside the lungs with a tube-shaped camera. Through the camera, the pulmonologist can obtain liquid and tissue samples to be reviewed by a pathologist.

A cardiothoracic surgeon, a surgeon specializing in surgeries involving the heart, lungs, vessels and other organs in the chest cavity, in addition to taking a thorough medical history and performing a medical exam may choose to perform an operative procedure to obtain tissue samples of lungs and lymph nodes in the chest.

What can you expect once you have been diagnosed with lung cancer?
Your doctor will discuss with you
a. the type of cancer you have (based on pathology reports)
b. whether it has spread to other places in your body, like organs or lymph nodes (based on radiologic studies: x-rays, CT scans, PET scans OR based on surgical pathology)
c. what your options are for treatment or palliation (palliation refers to treatment that is NOT designed to cure, but rather to improve the quality of your remaining life)
d. what you would like to do

Your doctor will also likely consult a surgeon, an oncologist or a radiation oncologist to help you understand all of the options available to you. An oncologist is a doctor who specializes in the evaluation and treatment of cancer.

You may want to have a loved one or trusted friend with you when you talk to your doctor about your diagnosis. There will be so much information, and the diagnosis of cancer is very frightening, that you may not be able to remember everything that is said to you. Another person may be able to help you remember information after your appointment, and may also help prompt additional questions for your physician.

While receiving a diagnosis like cancer is stressful, to be forewarned is to be forearmed!

Now is the time to say the things that need to be said, and to do the things that need to be done! Tell your family and friends important things like how much they have meant to you. Say "I love you" to everyone you love. Forgive people, AND TELL THEM THAT YOU FORGIVE THEM! You will feel at peace with yourself, and others will have the joy of knowing how much you care about them! Far too often, family members who have not spoken for years arrive too late, only to find that they missed their last chance to say "I'm sorry" or "I love you". Many people live with the guilt and sadness for the rest of their lives.

Think about what kind of medical treatment you would like to have. Are you someone who wants to fight with all your might, struggling to the bitter end to live every moment, no matter the cost to you? Are you someone who wants to enjoy the last weeks, months or years of your life loving family and friends and taking care of your private affairs? Or, are you somewhere between the two?

Thoughtful, sincere discussions with family members and friends about the kind and extent of medical treatment you would like to receive is very important. From these family and friends you may want to choose a special "spokesperson" to express your desires in the event that you are unable to do so. Just as you will need a Durable Power of Attorney to take care of your private business matters, you will need a Durable Power of Attorney for Health Care to assist with medical decision making when you are unable to do so. You will need someone you can trust to make decisions that you would otherwise make for yourself.

One thing to remember is that YOU are the captain of your ship! Only YOU can make decisions that are best for you!

Malignant Mesothelioma

Malignant Mesothelioma

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Malignant Pleural Mesothelioma Martha Burk, MD, MS WHMC/BAMC/UTHSCSA Combined Pulmonary Fellows’ Conference February 2005 People We Know Steve McQueen, 1980 Navy Admiral Elmo Zumwalt, 1999 Minnesota Congressman Bruce Vento, 2000 Evolutionary biologist Dr. Stephen Jay Gould, 2001 Epidemiology  80% cases associated with documented asbestos exposure  Highest risk associated with crocidolite, chrysolite and amosite  Other etiologies implicated    Therapeutic radiation Intrapleural thorium dioxide Inhalation of other fibrous silicates  Erionite or zeolite  Latency period 20-40+ years  Peak mortality expected in 2020-2030  Median survival  8-18 months from time of diagnosis  Lifetime risk of MM among asbestos workers is 8-13%  Annual incidence with exposure increases  3.5X for males  1.4X for females Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Asbestos fibers  Serpentine  Curly, pliable  Amphiboles   Crocidolite, amosite, tremolite, anthrophyllite, actinolite Long, needle-like www.som.tulane.edu/.../ AsbestosMinerals.jpg Incidence of MPM Countries UK and Netherlands Western Europe Germany, Spain, Ireland Eastern Europe United States South Africa Western Australia Males (per 100K) 7.4-8.8 2.9-4.2 1-1.9 0.6-1.0 1.5-2.2 >5.4 >4.8 Females (per 100K) 0.8-1.3 0.7-1.3 0.2-0.5 0.3-0.5 0.3-0.4 >2.3 >0.3 Treasure, T and Sedrakyan, A Pleural mesothelioma: little evidence, still time to do trials Lancet 2004 364:1183-1185 U.S. Mortality 1999 Table 7-1. Malignant mesothelioma: Number of deaths by sex, race, and age, and median age at death, U.S. residents age 15 and over, 1999 Site No. of Deaths Underlying Cause (%) Sex Race 15 24 25 34 3544 Age Group (yrs) 45 54 5564 6574 7584 Median Age (yrs) M F W B O 85+ Pleura 252 90.1 219 33 240 10 2 - - 2 12 32 101 86 19 72.0 Peritoneum 92 90.2 62 30 90 2 - - - 2 10 23 31 20 6 69.5 Other Sites 427 90.4 345 82 407 14 6 1 2 3 23 61 134 154 49 74.0 Unspecified 1,773 92.9 1,424 349 1,673 83 17 1 2 26 94 279 572 654 145 73.0 Any Site 2,485 94.3 1,995 490 2,355 105 25 2 4 33 13 8 389 818 888 213 73.0 Center for Disease Control, National Institute for Occupational Safety and Health All Cause Mortality in U.S. in 1999 Compressed Mortality Data for Years: Location: 1999-1999 The United States (FIPS=00) 25-34 years through 85 years and over All Races Age Description 25-34 years 35-44 years 45-54 years Death Count 41,066 89,256 152,974 238,979 452,600 698,590 646,141 Population 40,178,406 45,076,677 36,577,819 23,778,026 18,418,909 12,224,914 4,154,018 Crude Death Rate 102.2 198.0 418.2 1,005.0 2,457.3 5,714.5 15,554.6 Ages: Race: Gender: 55-64 years Both Genders 65-74 years Grouped by: Age 75-84 years 85 years and over Crude Rate Calculated per: 100,000 Total Deaths = 2,319,606 Total Population = 180,408,769 (age > 25) Suggested Citation: United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF 1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database. Statistics From 1999 # deaths from mesothelioma = 2,485 = 0.00107 Total # deaths all causes 2,319,606 (0.1%) # deaths from mesothelioma = 2,485 = 0.000014 Total U.S. Population 180,408,769 (0.0014%) United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF 1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database. Litigation Crisis Legal Costs/Societal Impact Senate Testimony by Steven Kazan. "Economic Cancer," Lawyer News, September 23, 2002 . . .2001 actuarial study that estimates the cost of asbestos litigation in the United States eventually reaching $200 billion, a legal liability situation that has already bankrupted nine defendants in the past year. It goes on to analyze a new report by the Rand Institute for Civil Justice that claims the asbestos litigation has spread to touch 85% of corporate America. www.kazanlaw.com *200 billion is approximately 2% of the Gross National Product for 2000 Occupations at Risk Mortality by Occupation Table 7-8. Malignant mesothelioma: Proportionate mortality ratio (PMR) adjusted for age, sex, and race by usual occupation, U.S. residents age 15 and over, selected states, 1999 95% Confidence Interval LCL 585 057 575 156 Plumbers, pipefitters, and steamfitters Mechanical engineers Electricians Teachers, elementary school 18 6 12 13 4.76 3.04 2.42 2.13 2.81 1.11 1.25 1.13 UCL 7.51 6.62 4.22 3.64 COC Occupation Number of Deaths PMR COC = Census Occupation Code The PMR is defined as the observed number of deaths with the condition of interest in a specific industry/occupation, divided by the expected number of deaths with that condition. Center for Disease Control, National Institute for Occupational Safety and Health Asbestos Trivia  Low level of asbestos fibers found in general public  Urine, feces, mucus  Found in environment, drinking water, etc.  Rural air typically contains 10 fibers/cubic meter   A typical person breathes about 1 cubic meter air in 1 hour City levels of asbestos fibers are generally 10X higher  Asbestos containing homes typically contain 30-60,000 fibers/cubic meter  EPA proposal limits concentration of asbestos fibers to 7 million fibers (>5 microns in length)/liter drinking water   Most drinking water contains < 1 million fibers/liter Some have as much as 10-300 million fibers/liter  OSHA limits the number of fibers 5 microns or larger to 100,000/cubic meter of workplace air for 8 hour shifts  July 12, 1989 EPA banned new uses of asbestos  Uses established prior to this date are permissible www.atsdr.cdc.gov/toxprofiles Environmental Risks  Rates of MPM development highest in Anatolia region of Turkey 50% of males from one village died of MPM  Six family clusters identified    Possible 6 generation pedigree Autosomal dominant pattern of inheritance with incomplete penetrance  May represent genetic predisposition Volcanic tuffs Pathogenesis  Exact mechanism of carcinogenicity unknown  Carcinogenicity associated with fiber length   >5 microns length <2.5 micron diameter  Inhaled fibers engulfed by macrophage  Long fibers not cleared, and chronic inflammatory process ensues Level and duration of exposure Time since exposure occurred Age at time of exposure Tobacco history Type and length of fibers  Magnitude of risk depends on       Asbestos fibers induce rat protooncogenes  c-fos, c-jun Deletions of 1p, 3p, 9p, and 6q Loss of chromosome 22 Defined and putative tumor suppressing genes SV40 virus  Multiple chromosomal abnormalities associated with MM     Potential Mechanisms for Damage Inhalation of asbestos fibers Chrysotile fibers biodegraded Biopersistence of crocidolite Fibers phagocytosed by macrophages, mesothelial cells and fibroblasts Mesothelial cells release IL-8, Monocyte chemoattractant protein-1, fibronectin Inflammatory cell recruitment, fibroblast and mesothelial cell proliferation Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Potential Mechanisms of Carcinogenicity Inhalation of Asbestos Fibers Fibers engulfed by macrophage Inflammatory response Oxygen radicals released Induction of DNA repair enzymes Aneuploidy Chromosomal damage Autophosphorylation Of Epidermal Growth Factor Receptor Increased expression C-fos, C-jun DNA synthesis Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Mitotic spindle interference Potential Role of Simian Virus 40  A DNA tumor virus  First suspected in 1991   60% hamsters with SV40 injected into their hearts developed pleural mesothelioma in the absence of asbestos exposure 100% hamsters developed pleural mesothelioma after SV40 injected intrapleurally  In some studies, as many as 50% human mesothelioma tumors coexpress SV40   Not applicable to other countries (Turkey, Finland) May be related to SV40 infected polio vaccines Disrupts genes, including tumor suppressing genes Produces proteins capable of inhibiting tumor suppressor genes, DNA repair Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers  SV40 DNA inserts itself into host DNA   Clinical Presentation  Mean age approximately 60 years  Early stage  Dyspnea, non-specific pleurisy, moderate effusions Moderate chest tightness Progressive pain, cough, dyspnea Dullness to percussion Palpable chest wall mass Approximately 10% have bilateral involvement at presentation  Later stages      Usually unilateral disease   Death usually is due to progressive dyspnea and respiratory insufficiency  Metastasis seen in approximately 50% at autopsy Presenting Symptoms Retrospective study of 322 Canadian patients with MM: 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% pn ys st De Ch in Pa ea ral eu ions Pl us Eff 90 84 29 3 t i gh We s s Lo <1 ti ma pto c 3 is tys a gh p u Co ver e mo hagi e Fe petit H ysp r’s D rne Ap s Ho lo s ym As Ruffie P et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 322 patients Journal of Clinical Oncology 7(8):1157-68, 1989. Traditional Staging Butchart, 1976 LOCALIZED I Disease confined within the capsule of the parietal pleura: ipsilateral pleura, lung, pericardium and diaphragm METASTATIC II III Stage I plus positive intrathoracic LNs Local extension into: chest wall or mediastinum, heart, diaphragm, peritoneum, with/without extrathoracic or contralateral LNs IV Distant metastatic disease Not a valid tool for stratifying for survival outcomes Pistolesi, M and Rusthoven, J Malignant pleural mesothelioma CHEST 2004 126:1308-1329 Malignant mesothelioma. Proposed Tumor Staging 7th World Conference of the International Association for the Study of Lung Cancer T1a T1b T2 Ipsilateral pleura T1a + foci tumor in visceral pleura T1b + diaphragm, confluent visceral tumor or pulmonary parenchyma T3 T1b + endothoracic fascia, mediastinal fat, solitary chest tumor or non-transmural pericardium T4 T1b + diffuse chest wall tumor, transdiaphragmatic peritoneum, contralateral pleura, mediastinal organ, spine or transmural pericardium or myocardium N0 No regional lymph node mets N1 Ipsilateral bronchopulmonary or hilar lymph node N2 Ipsilateral mediastinal lymph node, subcarinal lymph node, internal mammary node N3 Ipsilateral supraclavicular node, contralateral mediastinal node, internal mammary node, supraclavicular node M0 No distant mets M1 Distant mets Ia Ib II III T1a N0 M0 T1b N0 M0 T2 N0 M0 Any T3 M0 Any N1 M0 Any N2 M0 IV Any T4 Any N3 Any M1 Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Malignant Mesothelioma www.nci.nih.gov/cancertopics Investigative Options An Open and Closed Case Radiographic Findings  Extensive nodular or lobular thickening of pleura  Pleural effusions  Asbestos related plaques  Chest wall, bone or organ invasion best seen by CT or MRI Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 Pleural Thickening sprojects.mmi.mcgill.ca/. ../plpsdo_radio.htm Pleural Plaques Emedicine.com Pleural Mass Emedicine.com CT v MRI in Asbestos-related Pleural Disease  21 pts with confirmed long-term asbestos exposure  CT and MRI    4 readers Interobserver agreement for pleural plaque detection was moderate for both  Kappa 0.72 for MRI, and 0.73 for CT  Considered ‘good’ agreement  Sens MRI 88% Pleural thickening, pleural effusion  Interobserver agreement better with MRI Weber, et al. Asbestos-related pleural disease: value of dedicated magnetic resonance imaging techniques Invest Radiol 2004 39:554-564 PET v CT  Retrospective review 18 pts with MPM  Utility of PET in detecting  Mediastinal LNs  Distant metastases CT Sens Spec PPV NPV 43 56 43 56 PET 100 82 71 100 CT True + True False + False Conclusions 3 5 4 4 PET 5 9 2 0 1. MPM metastasizes more commonly than previously thought 2. PET is better than CT for staging 3. May aid in better selection of candidates for aggressive multimodality therapy 4.Benard, et al found Sens 83%, Spec 75% Schneider, et al Positron emission tomography with F18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma Thorac Cardiovasc Surg 2000 120:128-33 Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722 MRI and PET Images Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722 Value of PET in T Status T Status by PET T0-T3 Surgical/Pathologic T status Total # Patients T0-T3 T4 29 17 46 T4 3 4 7 Total # Patients 32 21 53 Conclusion: PET is relatively poor at defining locoregional disease Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma J Thorac Cardiovasc Surg 2003 126:11-15 Value of PET in N Status N Status by PET N0 and N1 19 8 27 N2 3 1 4 Total # Patients 22 9 31 Pathologic N Status N0 and N1 N2 Total # Patients Conclusion: PET may be useful in assessing node status Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma J Thorac Cardiovasc Surg 2003 126:11-15 Thoracentesis        Highly viscous Often bloody Exudative Lymphocyte predominant Protein 4-5 g/dl LDH often >600 IU/l Pleural fluid cytology often inadequate    Mesothelioma Diagnosis achieved in 20-30% cases Epithelioid mesothelioma Adenocarcinoma similar to adenocarcinoma Sarcomatous type similar to fibrosarcoma, hemangiopericytomas Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial Lancet 2003 361:1326-31 Imp.ualberta.ca Dpalm.med.uth.tmc.edu Cytology  Criteria for identifying MPM are not highly specific  Abundance of cells with cytoplasmic characteristics of mesothelioma cells       Abundant dense cytoplasm Cell engulfment Intercellular windows Small peripheral vacuoles Presence of collagen and/or basement membrane-like material and hyaluronic acid in background Orangiophilic squamous-like cells Whitaker, D The cytology of malignant mesothelioma Cytopathology 2000 11:139-151 Closed Pleural Biopsy  Often provides inadequate tissue for diagnosis  Diagnosis achieved in approximately 20% cases  Pleural fluid cytology + closed pleural biopsy results in a diagnosis approximately 35-40%  Effectively increases yield by 7-26% UK study of 47 pts with suspected malignant pleural effusions 20 pts had a final diagnosis of MPM Sens Spec NPV PPV Abram’s 55% 100% 72% 100% CT-guided 88% 100% 94% 100% Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial Lancet 2003 361:1326-31  Abram’s needle versus CT-guided biopsy   Thoracoscopy  Indications   Mesothelioma suspected Tissue diagnosis not confirmed  95% diagnostic yield in malignancy  Able to visualize tumor   Firm, gray Thick rind Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722 Gross Pathologic Appearance Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722 Histology Classifications of Malignant Pleural Mesothelioma Epithelial  Comprises ~ 54% of all MPM  Large nuclei with prominent nucleoli Epithelioid Mesothelioma  Eosinophilic cytoplasm  Can mimic other tumors  Example: adenocarcinoma, giant cell, small cell, clear cell, signet cell, glandular, myxoid, microcystic and adenoid cystic carcinomas Adenocarcinoma www.mesothelioma-asbestos-lung-cancer.com/ inf... Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 Edcenter.med.cornell.edu Sarcomatoid  ~ 21% of MPM  Less common Sarcomatoid Mesothelioma  More aggressive  Spindle-shaped cells resembling fibrosarcomas and leiomyosarcomas Fibrosarcoma www.mesothelioma-asbestos-lung-cancer.com Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 www.geocities.com Mixed  Approximately 25% of all MPM  Features of epithelioid and sarcomatoid Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 Diagnostic Aids Technique Histology Periodic Acid Schiff Mucicarmine Immunostaining Carcinoembryonic Assay Leu M-1 Vimentin Cytokeratin Electron microscopy MPM Negative Negative Negative Negative Positive Positive Long microvilli Adeno CA Positive Positive Positive (75%) Positive Negative Negative Short microvilli Whitaker, D The cytology of malignant mesothelioma Cytopathology 2000 11:139-151 Asbestos Fibers www.medicine.creighton.edu Immunostaining Fig. 2A. Malignant mesothelioma, mixed type, stained for calretinin. The epithelial component is strongly stained, while the sarcomatous component is moderately stained. Fig. 2C. Cell block from pleural exudate with adenocarcinoma stained for calretinin. The normal mesothelial cells are stained, while tumour cells are unstained. www.nordiqc.org Treatment Palliation v Aggressive Therapy Pleurodesis  Viallat, et al CHEST 1996 evaluated the efficacy of thoracoscopic talc poudrage in malignant pleural effusions   360 patients 24% had MPM Mesothelioma N=85 Pleural mets N=242 Overall N=327 Complete Response % Partial response % Failure % 78.8 5.9 15.3 88.5 3.7 7.8 85.9 4.3 9.8 Poudrage = thoracoscopic application of sclerosing agent with sprayer Pneumatic pump sprayer used in this study Viallat, et al Thoracoscopic talc poudrage pleurodesis for malignant effusions CHEST 1996 110:1387-93 Definitions  P/D (Pleurectomy/Decortication)  Removal of  Visceral, parietal, pericardial pleura from apex of lung to diaphragm  EPP (Extrapleural pneumonectomy)  En bloc resection of     Visceral and parietal pleura Lung Pericardium Ipsilateral diaphragm Pistolesi, M and Rusthoven, J Malignant pleural mesothelioma: update, current management, and newer therapeutic strategies CHEST 2004 126:1318-1329 Pleurectomy in MPM  Results of pleurectomy trials Author Location Martini et al Memorial Sloan-Kettering Ca Ctr Achatzy et al Germany Brancatisano et al Australia Soysal et al Turkey Year 1975 1989 1991 1997 # Patients 14 118 45 100 % Morbidity 22 6 16 22 % Mortality Median survival 10 8.5 2.2 1 9 months 16 months Roberts, J Surgical treatment of mesothelioma: pleurectomy CHEST 1999 116:446s-449s Pleuropneumonectomy  Aggressive cytoreductive component of multimodality therapy       EPP, chemo, adjuvant radiotherapy Appropriate for only a minority of MPM patients General exclusion criteria include:  FEV1 <1 L/min  EF <45%  Room air PCO2 >45  Room air PO2 <65 Operative mortality rate approximately 4% Overall morbidity is about 24% Survival rates  Overall 36% and 14% (2 and 5 years, respectively)  Epithelial tumors 52% and 21%  Sarcomatous or Mixed tumors 16% and 0% Conclusions  Survival increased for a select few  Morbidity remains high  No reference to quality of life Grondin, S and Sugarbaker, D  Pleuropneumonectomy in the treatment of malignant pleural mesothelioma CHEST 1999 116:450S-454S Survival After Surgery Overall Survival  120 pts  MPM Butchart Stage I  Good performance status Survival Based on Node Status  EPP with adjuvant chemoradiation therapy  Positive nodes indicate worse prognosis Sugarbaker and Garcia Multimodality therapy for malignant pleural mesothelioma CHEST 1997 112:272-275S Chemotherapy  No single therapy has consistently improved survival by >20%  Phase II study of gemcitabine with cisplatin associated with a 48% response rate without improvement in survival  Phase III study of pemetrexed (antifolate agent) and cisplatin versus cisplatin     Survival 12 v. 9 months Time to progression 6 v. 4 months Significant neutropenia and leukocytopenia  Despite B12 and folate supplementation Most common SEs (nausea, vomiting, fatigue) 150 patients with inoperable MPM 15% response rate 69% had stable disease 69% achieved improvement in symptoms     Mitomycin C, Vinblastine and Cisplatin     71% had decreased pain 62% had decreased cough 50% had decreased dyspnea  Median overall survival 7 months Kindler, H Malignant pleural mesothelioma Curr Treat Options Oncol 2000 1:313-326 Vogelzang, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma J Clin Oncology 003 21:2636-2644 Andreopoulou, et al. The palliative benefits of MVP chemotherapy in patients with malignant mesothelioma Ann Oncol 2004 15:1406-12 Survival With Chemotherapy      Histologically confirmed mesothelioma Good functional status Expected to survive > 2 months No prior chemotherapy “Adequate” organ function # Eligible Patients 37 39 41 41 18 20 35 % Response Rate 26 14 7 17 12 25 9 Median Survival (Mos) 8.1 8.8 7.1 6.7 3.9 9.6 5.0 Treatment Regimens Mitomycin & Cisplatin Doxorubicin & Cisplatin Carboplatin DHAC Trimetrexate Edatrexate Paclitaxel Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treatedbetween 1984 and 1994 by the cancer and leukemia group b CHEST 13:723-31 Survival Predictors N = 337 Excellent Performance Status Age < 49 12.5 mos Age > 49 Hgb > 14.6 14.5 mos Poor Performance Status WBC < 15.6 Chest Pain Weight Loss WBC > 9.8 Hgb > 11.2 9.6 mos Hgb < 11.2 4.9 mos WBC > 15.6 1.4 mos Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the cancer and leukemia group b CHEST 13:723-31 Pemetrexed and Cisplatin Survival Disease Progression Vogelzang, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma J Clin Oncology 003 21:2636-2644 Radiation  No survival benefit to radiation therapy alone  Side effects limit dose  Higher doses radiation tolerated after EPP  Small field dosing effective at decreasing biopsy tract seeding  Effective in palliative care Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies CHEST 2004: 126:1318-1329 Radiation Therapy Trials Investigators # of Patient s 3 12 6 23 14 9 Dose Outcome (cGy) 20003000 50005500 >4000 >4000 35005000 6000 Symptomatic improvement 1 asymptomatic x 4 yrs, 2 effusion controlled 4 symptomatic relief 1 symptomatic relief 4 alive at 1-41 mos, 10 dead at 1-37 mos. Median survival 15 mos 2 local control of cancer at 20-40 months 66 symptomatic improvement median survival 5 months University of Iowa Brompton/Royal Marsden Joint Center for Radiotherapy Institute GustaveRoussy Thomas Jefferson Medical Center Peter MacCallum Cancer Institute 111 8-60 Chun et al., http://www.vh.org/adult/provider/radiology/LungTumors/Mesothelioma/Text/MesoRadiation.html Mesothelioma Treatment Trials Study # Pts Age Yrs 57 mean 53 median 62 median <60 69 median 59 mean 57 median F (%) Epithelioid (%) 56 100 68 54 73 79 87 Treatment In-Hospital deaths 3.8 6.2 7.9 9.1 6.9 NA 7.5 Median Survival (months) 19 Unclear 17 35 18 24 17 65% 1yr survival EPP v debulking No statistical significance Sugarbaker 4% mortality 1999 50% morbidity 6% mortality 183 32 61 51 26 28 53 73 33 17 19 7 - EPP/C/R EPP/C/R EPP/R EPP/C EPP/C/R EPP/R EPP/R R Not extensive OR 3.0 non epith 1.7 + margin 2.0 EP nodes I (6) II (10) III (16) Survival 33.8 m I-II 10 m III-IV 90/70-T1 85/36-T2 1/3 yr survival Maggi 2001 Rusch 2001 Aziz 2002 Lee 2002 Ahamad 2003 8% mortality 9% mortality 6% mortality 8.5% mortality Stewart 2004 Treasure and Sedrakyan Pleural mesothelioma: little evidence, still time to do trials Lancet 2004 264:1183-85 Treatment Options: Local Disease  Solitary mesotheliomas  Surgical resection en bloc  Intracavitary mesothelioma  Palliative surgery   Pleurectomy and decortication With/without postoperative radiation   Extrapleural pneumonectomy Palliative radiation  Pleural effusions  Pleurodesis Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies CHEST 2004: 126:1318-1329 Treatment Options: Advanced Disease  Symptomatic treatment   Drain effusions Pleurodesis  Palliative surgical resection in select patients  Palliative radiation  Chemotherapy  Permetrexed (antifolate) and cisplatin increases survival by approximately 3 months  Multimodality clinical trials  Intracavitary chemotherapy  Better results seen with intraperitoneal mesothelioma Association of Cancer Online Resources Assessing Quality of Life  Chest pain and dyspnea are the most common symptoms at presentation  Questionnaires frequently used to assess QOL  European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30)  Lung Cancer Module (QLQ-LC13)  Nowak, et al., 2004 validated use of above questionnaires  At time of diagnosis, role function and social function more impaired than previously suspected  Worst rated symptoms       Fatigue Dyspnea Pain Insomnia Appetite loss Cough  Dyspnea scores correlated well with FVC Nowak, A, Stockler, M, Byren, M Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module J Clin Oncol 2004 22:3172-3180 Management  Treatment of advanced disease is largely palliative    Chemotherapy Surgery Radiation      Doxorubicin produces partial response in 15-20% No single agent induces > 20% response Operative mortality pleurectomy/decortication < 2% Mortality with extrapleural pneumonectomy 6-30% Radiation useful to alleviate pain  Duration short Talc pleurodesis effective and inexpensive Thoracoscopic pleurodesis more effective than medical pleurodesis  Pleural sclerosis minimizes recurrent pleural effusions   Prognostic Indicators  Poor prognosis      Thrombocytosis Fever of unknown origin Sarcomatous or mixed histology Age > 65 Poor performance status Epithelial histology Stage I disease Good performance status Absence of chest pain Symptomatic < 6 months prior to diagnosis Absence of weight loss Absence of involvement of visceral pleura  Better prognosis        Summary  Smoking NOT associated with increased risk of developing MPM   HOWEVER, smoking increases risk of developing bronchogenic carcinoma when combined with asbestos exposure! Risk approximately 50x greater  Thorough occupational history helpful at determining pts at risk  ~30% of patients have no known exposure to asbestos  CT-guided biopsy may be more cost-effective than thoracentesis  PET useful in early detection of LN involvement and distant mets  MPM metastasizes earlier than once thought  Pts with negative LNs benefit from aggressive multimodality therapy  Pts with advanced disease benefit from palliative therapy www.lung.ca/diseases/cancer References Benard, et al Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography CHEST 1998 114:713-722 Center for Disease Control, National Institute for Occupational Safety and Health Community Health Sciences Dept., St. George’s Hospital Medical School Dpalm.med.uth.tmc.edu Emedicine.com Grondin, S and Sugarbaker, D Pleuropneumonectomyin the treatment of malignant pleural mesothelioma CHEST 1999 116:450S-454S Flores, et al Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma J Thorac Cardiovasc Surg 2003 126:11-15 Herndon, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the cancer and leukemia group b CHEST 13:723-31 Imaging of Diseases of the Chest. Armstrong. Mosby. Toronto 2000 Imp.ualberta.ca Kindler, H Malignant pleural mesothelioma Curr Treat Options Oncol 2000 1:313-326 Light, Richard. Textbook of Pleural Disease 2003 Arnold Publishers Malignant mesothelioma. www.nci.nih.gov Maskell, et al. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial Lancet 2003 361:1326-31 Mesotheliomacenter.org Nowak, A, Stockler, M, Byren, M Assessing quality of life during chemotherapy for pleural mesothelioma: feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module J Clin Oncol 2004 22:3172-3180 Pistolesi, M and Rusthoven, J. Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies CHEST 2004 126:1318-1329 Roberts, J Surgical treatment of mesothelioma: pleurectomy CHEST 1999 116:446s-449s Ruffie P et al. "Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 322 patients." Journal of Clinical Oncology 1989 7(8):1157-68 Schneider, et al Positron emission tomography with F18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma Thorac Cardiovasc Surg 2000 120:128-33 Seattlepi.nwsource.com Treasure, T and Sedrakyan, A Pleural mesothelioma: little evidence, still time to do trials Lancet 2004 364:1183-1185 United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF 1968-1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database. Viallat, et al Thoracoscopic talc poudrage pleurodesis for malignant effusions CHEST 1996 110:1387-93 Vogelzang, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma Journal of Clinical Oncology 2003 21:2636-2644 Whitaker, D The cytology of malignant mesothelioma Cytopathology 2000 11:139-151 www.atsdr.cdc.gov/toxprofiles www.kazanlaw.com www.lung.ca/diseases/cancer www.som.tulane.edu/.../ AsbestosMinerals.jpg Kappa  Measure of agreement between two observers Interrater reliability  A descriptor rather than an indicator of statistical significance κ = Observed – Expected agreement 1 – Expected agreement  Excellent agreement Very good agreement Fair agreement Poor agreement No agreement 0.93 – 1.0 0.81 – 0.92 0.41 – 0.60 0.01 – 0.20 ≤ 0.00 Basic & Clinical Biostatistics. 3rd ed. Beth Dawson and Robert Trapp. Behavior Modeling . . . Aiding The War Effort . . . Immediate Release January 22, 1943 The men who sail the ships of the American merchant marine will soon be supplied with free cigarettes for use during long voyages with materials for the war effort, the War Shipping Administration announced today. Through an arrangement with a leading cigarette manufacturer, the WSA has established a program whereby the cigarettes will be distributed free of charge to seamen aboard all vessels of the Victory Fleet. The idea was presented to the WSA by the manufacturer as a contribution to the war effort. Cigarettes will be made available to merchant seamen immediately. Shipments are to be made to representatives of the WSA at various ports and will be marked "For distribution to Seamen of the Merchant Marine." WSA officers in the ports will insure distribution in the proper manner. http://www.usmm.net/cigarette.html