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State of the Art: Clinical Review of Lung Cancer
=
----1. 11. CHES~LUME
91 I
NUMBER
3 I MARCH, 1987 Supplement
Introduction
I
n 1986 lung cancer became the dominant fatal neoplasm of our time. Not only is it now the most common cause of cancer-related death in men, but also it is the most common cause of cancer death in women. This year more than 135,000 cases oflung cancer will be diagnosed in the United States. Soon, lung cancer will be the most common cause of death due to cancer in the world . The vast majority of people so affected will die in spite of radiation treatment, chemotherapy and surgery. Therefore, it is vitally important that we gain new understanding of the factors that predispose indi viduals to lung cancer and of the molecular and cellular activities involved in the pathogenesis oflung cancer. For the first time in its history, the Aspen Lung Conference considered the molecular and cellular biology of lung cancer. This conference, which was held at the Given Institute of Pathobiology from June 11-14, 1986, attracted investigators from throughout the world to meet and consider current understandings of lung cancer and to determine the future directions research must take .
Charles Scoggin, M.D ., F.C.C .P., Chairman Denver
session 1 State of the Art: Clinical Review of Lung cancer Presented by: Edward Sawville, M.D .* Reported by: Charles Scoggin, M.D ., F.C.C.P.
cancer has been termed a "medical, social and political scandal." Lung has been the only site with a consistent increase in mortality due to cancer. Because of its prevalence, it literally effects the lives of millions of people in our society. The four main types oflung cancer are: small cell cancer, squamous cell lung cancer, large cell anaplastic lung cancer, and adenocarcinoma of the lung. Each accounts fur 15% to 25% of all types of lung cancer. These lung cancers show differences in histology and clinical characteristics that bespeak a fundamental difference in the basic biology of the tumors. With techniques of molecular biology, these differences now can be studied. Screening of patients at risk fur lung cancer appears to change the stage at which patients are detected, but not necessarily overall mortality. This is to say that more patients ~ng
*From the National Cancer Institute-Navy, Bethesda.
were found at an earlier stage of the disease. In general, patients who are candidates fur screening studies are smoking men more than 45 years old, particularly those working in industries associated with radiation exposure. The primary therapeutic considerations for patients depends on the cell type. Localized non-small cell lung cancer can be treated with surgical resection or irradiation for cure. Disseminated disease is best managed with palliative irradiation; however, chemotherapy may be effective in selected cases . Small cell carcinoma, on the other hand, both localized and disseminated, should be managed with combination chemotherapy with or without chest irradiation. Overall, cancer survival for all forms of lung cancer is 5 to 10%. Patients with non-small cell lung cancer surgically resected for cure have approximately a 20% survival rate . Small cell lung cancer presents distinctive features. It is charactized by having a rapid growth rate; early, widespread metastasis; frequent central endobronchial site of tumor; regional node involvement; associated paraneoplastic syndromes; and a high response to chemotherapy and irradiation . In managing small cell lung cancer, the major question is whether or not the patient has localized (limited) or nonlocalized (extensive) disease. Therefore, the workup of patients is directed at differention between limited and CHEST I 91 I 3 I MARCH, 1987 I Supplement
15
extensive disease. Assignment of the patient to a limited stage category raises the possibility of benefit from chest irradiation and response to drugs with three- to four-agent chemotherapy to a 70% survival rate. Approximately 12 to 15% of patients with limited-stage small cell lung cancer survive 6 to 11years. An occasional patient can have a relapse at six years. Patients successfully treated are at risk for other non-small cell cancers, as well as other forms of cancel; and a distinct neuropsychologic abnormality thought to be related to both cranial irradiation and, possibly, chemotherapy. Non-small cell lung cancer stages 1 and 2 should be treated with surgical resection. Additional chemotherapy or irradiation has not as yet been shown to affect survival in stage 1 carcinoma. Adjuvant radiation therapy has been shown to have an absent or negative effect on survival. However, it does decrease the rate of local recurrence of tumor; A consistently small but reproducible group of patients with non-small cell lung cancer limited to the chest alone do appear to benefit from radiation for cure. It is to be emphasized, however; that because of the effects of irradiation on the lung, such patients must have pulmonary function equivalent to that necessary for pneumonectomy. Currently, there are trials underway to determine the role of chemotherapy in non-small cell lung cancel: This should be performed only as part of the clinical trial. While approximately 30 to 37% of patients respond to chemotherapy, it is difficult to demonstrate any effect on long-term survival.
Are Coal Miners at Increased Risk
for scar cancer?*
v Vallyathan, Ph.D.; R. Althouse, M.S.; F. H. 1: Green, M.D.; C. Boyd, M.D.; and N. Rodman, M.D.
T
he relationship between scarring of the lung and the development of lung cancer has been a topic of great interest. It has been suggested that scarring of the lung is a predisposing factor in the development of cancer and serves as a nidus of growth. Many pathogenic factors, such as exposure to asbestos, beryllium and silica, and focalfibrosing factors, such as injury, tuberculosis, pneumonia and infarct, have been implicated as etiologic agents.r" On the other hand, Shimosato et al6 suggested that scarring results from a desmoplastic reaction to tumor, te, the tumor causes the scarring and the severity of scar is inversely correlated with survival. This hypothesis is supported by the recent studies on collagen subtypes associated with the scars in lung cancers. IS Repeated episodes of tumor necrosis also have been suggested as a mechanism of scar tissue formation. Although there is conflicting evidence concerning whether the fibrosis precedes the tumor or results from it, there is general agreement that scar cancers arise mostly in the upper lobes and are usually localized in the peripheral regions of lung. 3.1-8 Common histologic cell types are adenocarcinomas and bronchoalveolar cell carcinomas. Since coal *From the Division of Respiratory Disease Studies, National institute for Occupational Safety and Health and West Virginia University, Morgantown. ~nt re~: Dr. Vallyathan, Pathology Section, NIOSH, 944 Chestnut Ridge Road, Morgantown, We8t Virginia 26505
28
workers' pneumoconiosis (CWP) frequently occurs in the upper lobes, and more than 45% of the tumors in the National Coal Workers' Autopsy Study (NCWAS) cases arise in the upper lobes, we designed a study to test the hypothesis that scarring due to coal mine dust exposure predisposes to lung cancer. If the hypothesis is correct, ie, that coal miners are at an increased risk for scar cancer, we would expect: (1) histologic evidence for the association of cancer with scar; (2) an increased occurrence of peripheral tumors with scar; (3) an increased proportion of adenocarcinomas with scar; (4) severe pneumoconiosis with coal dust in lung cancer cases. First, to assess the association of fibrosis with lung carcinoma, we used case control methodology to compare the type and severity of pneumoconiosis in the lungs of coal miners with primary lung cancer with that of coal miners without lung cancel: Of a total of 171 coal miners with pathologically confirmed primary carcinoma of the lung, 106 sets were matched with an equal number ofcoal miners without lung cancer by age at death ( ± 2), pack years of smoking ( ± 2), and years of underground mining ( ± 2). Second, to test the association of site of origin of lung tumor to CW~ we compared the lobar position of tumor to presence or absence of CWP within the lung cancer cases. Twopathologists graded and classified CWP in the cancer cases and matched controls according to criteria and standards recommended by the College ofAmerican Pathologists and the National Institute for Occupational Safety and Health." The lung tumors were cell-typed and classified according to the World Health Organization classification by four pathologists. The tumors and pneumoconioses were evaluated from multiple slides (minimum of three) stained with hematoxylin-eosin. In cases without unified consensus on diagnosis of cell type, special stains for keratin, mucin, and neurosecretory products and trichrome stain for connective tissue were used. Chi-square statistics, odds ratios, and McNemars statistics were used to test the relationships. The coal miners with lung cancer and matched controls without lung cancer had an average age of66 ± 9 years with an average 29 ± 14 years of underground coal mining history and an average 31 ± 23 pack years of cigarette smoking history. The predominant cancer in the coal miners' autopsy cases was squamous cell carcinoma followed by equal proportions of adenocarcinoma and small cell carcinoma. Adenocarcinomas showed a predominant peripheral origin (38%), whereas the squamous carcinomas tended to be originating more commonly in the larger airways (44%) and small cell carcinoma originated in the subsegmental bronchi (35%). Majority of the tumors (45%) originated in the upper lobes of the lungs. Comparison of the type of CWP in coal miners with and without lung cancer showed that, overall, 84% of the lung cancer cases had either simple or complicated CWP as opposed to 66% in the controls. McNemar's test of 106 matched pairs of lung cancer cases with controls showed a statistically significant relationship of lung cancer to simple CWP (p<.05), and a slight but nonsignificant increase of severe CWP in the lung cancer cases. There also was evidence of increased frequency of occurrence of simple CWP in the upper lobes of the lung in the 171 primary lung cancer cases but no similar trend with severe CWE Pulmonary fibrosis is frequently associated with lymphatic obstruction and accumulation of inhaled particulate dust. 29th Aspen LungConference
----1. 11. CHES~LUME
91 I
NUMBER
3 I MARCH, 1987 Supplement
Introduction
I
n 1986 lung cancer became the dominant fatal neoplasm of our time. Not only is it now the most common cause of cancer-related death in men, but also it is the most common cause of cancer death in women. This year more than 135,000 cases oflung cancer will be diagnosed in the United States. Soon, lung cancer will be the most common cause of death due to cancer in the world . The vast majority of people so affected will die in spite of radiation treatment, chemotherapy and surgery. Therefore, it is vitally important that we gain new understanding of the factors that predispose indi viduals to lung cancer and of the molecular and cellular activities involved in the pathogenesis oflung cancer. For the first time in its history, the Aspen Lung Conference considered the molecular and cellular biology of lung cancer. This conference, which was held at the Given Institute of Pathobiology from June 11-14, 1986, attracted investigators from throughout the world to meet and consider current understandings of lung cancer and to determine the future directions research must take .
Charles Scoggin, M.D ., F.C.C .P., Chairman Denver
session 1 State of the Art: Clinical Review of Lung cancer Presented by: Edward Sawville, M.D .* Reported by: Charles Scoggin, M.D ., F.C.C.P.
cancer has been termed a "medical, social and political scandal." Lung has been the only site with a consistent increase in mortality due to cancer. Because of its prevalence, it literally effects the lives of millions of people in our society. The four main types oflung cancer are: small cell cancer, squamous cell lung cancer, large cell anaplastic lung cancer, and adenocarcinoma of the lung. Each accounts fur 15% to 25% of all types of lung cancer. These lung cancers show differences in histology and clinical characteristics that bespeak a fundamental difference in the basic biology of the tumors. With techniques of molecular biology, these differences now can be studied. Screening of patients at risk fur lung cancer appears to change the stage at which patients are detected, but not necessarily overall mortality. This is to say that more patients ~ng
*From the National Cancer Institute-Navy, Bethesda.
were found at an earlier stage of the disease. In general, patients who are candidates fur screening studies are smoking men more than 45 years old, particularly those working in industries associated with radiation exposure. The primary therapeutic considerations for patients depends on the cell type. Localized non-small cell lung cancer can be treated with surgical resection or irradiation for cure. Disseminated disease is best managed with palliative irradiation; however, chemotherapy may be effective in selected cases . Small cell carcinoma, on the other hand, both localized and disseminated, should be managed with combination chemotherapy with or without chest irradiation. Overall, cancer survival for all forms of lung cancer is 5 to 10%. Patients with non-small cell lung cancer surgically resected for cure have approximately a 20% survival rate . Small cell lung cancer presents distinctive features. It is charactized by having a rapid growth rate; early, widespread metastasis; frequent central endobronchial site of tumor; regional node involvement; associated paraneoplastic syndromes; and a high response to chemotherapy and irradiation . In managing small cell lung cancer, the major question is whether or not the patient has localized (limited) or nonlocalized (extensive) disease. Therefore, the workup of patients is directed at differention between limited and CHEST I 91 I 3 I MARCH, 1987 I Supplement
15
extensive disease. Assignment of the patient to a limited stage category raises the possibility of benefit from chest irradiation and response to drugs with three- to four-agent chemotherapy to a 70% survival rate. Approximately 12 to 15% of patients with limited-stage small cell lung cancer survive 6 to 11years. An occasional patient can have a relapse at six years. Patients successfully treated are at risk for other non-small cell cancers, as well as other forms of cancel; and a distinct neuropsychologic abnormality thought to be related to both cranial irradiation and, possibly, chemotherapy. Non-small cell lung cancer stages 1 and 2 should be treated with surgical resection. Additional chemotherapy or irradiation has not as yet been shown to affect survival in stage 1 carcinoma. Adjuvant radiation therapy has been shown to have an absent or negative effect on survival. However, it does decrease the rate of local recurrence of tumor; A consistently small but reproducible group of patients with non-small cell lung cancer limited to the chest alone do appear to benefit from radiation for cure. It is to be emphasized, however; that because of the effects of irradiation on the lung, such patients must have pulmonary function equivalent to that necessary for pneumonectomy. Currently, there are trials underway to determine the role of chemotherapy in non-small cell lung cancel: This should be performed only as part of the clinical trial. While approximately 30 to 37% of patients respond to chemotherapy, it is difficult to demonstrate any effect on long-term survival.
Are Coal Miners at Increased Risk
for scar cancer?*
v Vallyathan, Ph.D.; R. Althouse, M.S.; F. H. 1: Green, M.D.; C. Boyd, M.D.; and N. Rodman, M.D.
T
he relationship between scarring of the lung and the development of lung cancer has been a topic of great interest. It has been suggested that scarring of the lung is a predisposing factor in the development of cancer and serves as a nidus of growth. Many pathogenic factors, such as exposure to asbestos, beryllium and silica, and focalfibrosing factors, such as injury, tuberculosis, pneumonia and infarct, have been implicated as etiologic agents.r" On the other hand, Shimosato et al6 suggested that scarring results from a desmoplastic reaction to tumor, te, the tumor causes the scarring and the severity of scar is inversely correlated with survival. This hypothesis is supported by the recent studies on collagen subtypes associated with the scars in lung cancers. IS Repeated episodes of tumor necrosis also have been suggested as a mechanism of scar tissue formation. Although there is conflicting evidence concerning whether the fibrosis precedes the tumor or results from it, there is general agreement that scar cancers arise mostly in the upper lobes and are usually localized in the peripheral regions of lung. 3.1-8 Common histologic cell types are adenocarcinomas and bronchoalveolar cell carcinomas. Since coal *From the Division of Respiratory Disease Studies, National institute for Occupational Safety and Health and West Virginia University, Morgantown. ~nt re~: Dr. Vallyathan, Pathology Section, NIOSH, 944 Chestnut Ridge Road, Morgantown, We8t Virginia 26505
28
workers' pneumoconiosis (CWP) frequently occurs in the upper lobes, and more than 45% of the tumors in the National Coal Workers' Autopsy Study (NCWAS) cases arise in the upper lobes, we designed a study to test the hypothesis that scarring due to coal mine dust exposure predisposes to lung cancer. If the hypothesis is correct, ie, that coal miners are at an increased risk for scar cancer, we would expect: (1) histologic evidence for the association of cancer with scar; (2) an increased occurrence of peripheral tumors with scar; (3) an increased proportion of adenocarcinomas with scar; (4) severe pneumoconiosis with coal dust in lung cancer cases. First, to assess the association of fibrosis with lung carcinoma, we used case control methodology to compare the type and severity of pneumoconiosis in the lungs of coal miners with primary lung cancer with that of coal miners without lung cancel: Of a total of 171 coal miners with pathologically confirmed primary carcinoma of the lung, 106 sets were matched with an equal number ofcoal miners without lung cancer by age at death ( ± 2), pack years of smoking ( ± 2), and years of underground mining ( ± 2). Second, to test the association of site of origin of lung tumor to CW~ we compared the lobar position of tumor to presence or absence of CWP within the lung cancer cases. Twopathologists graded and classified CWP in the cancer cases and matched controls according to criteria and standards recommended by the College ofAmerican Pathologists and the National Institute for Occupational Safety and Health." The lung tumors were cell-typed and classified according to the World Health Organization classification by four pathologists. The tumors and pneumoconioses were evaluated from multiple slides (minimum of three) stained with hematoxylin-eosin. In cases without unified consensus on diagnosis of cell type, special stains for keratin, mucin, and neurosecretory products and trichrome stain for connective tissue were used. Chi-square statistics, odds ratios, and McNemars statistics were used to test the relationships. The coal miners with lung cancer and matched controls without lung cancer had an average age of66 ± 9 years with an average 29 ± 14 years of underground coal mining history and an average 31 ± 23 pack years of cigarette smoking history. The predominant cancer in the coal miners' autopsy cases was squamous cell carcinoma followed by equal proportions of adenocarcinoma and small cell carcinoma. Adenocarcinomas showed a predominant peripheral origin (38%), whereas the squamous carcinomas tended to be originating more commonly in the larger airways (44%) and small cell carcinoma originated in the subsegmental bronchi (35%). Majority of the tumors (45%) originated in the upper lobes of the lungs. Comparison of the type of CWP in coal miners with and without lung cancer showed that, overall, 84% of the lung cancer cases had either simple or complicated CWP as opposed to 66% in the controls. McNemar's test of 106 matched pairs of lung cancer cases with controls showed a statistically significant relationship of lung cancer to simple CWP (p<.05), and a slight but nonsignificant increase of severe CWP in the lung cancer cases. There also was evidence of increased frequency of occurrence of simple CWP in the upper lobes of the lung in the 171 primary lung cancer cases but no similar trend with severe CWE Pulmonary fibrosis is frequently associated with lymphatic obstruction and accumulation of inhaled particulate dust. 29th Aspen LungConference