ENVIRONMENTAL RESEARCH 59, 145-149 (1992)
Advances in Lung Cancer? 1 ALVIN S. TEIRSTEIN
Mount Sinai School of Medicine, New York 10029 and Division of Pulmonary and Critical Care Medicine, The Mount Sinai Medical Center, New York 10029 Received M a y 15, 1992 Selikoff was among the first to emphasize the etiologic role of cigarette smoking and asbestos exposure in lung cancer. Recent reports suggest that aggressive chemotherapy and radiotherapy combined with surgery have improved the prognosis in lung cancer. The outc o m e of 100 patients with non-small-cell lung cancer (NSCLC) seen in 1979-1980 was c o m p a r e d with the outcome of 100 patients seen in 1989-1990. The two groups consisted of consecutive patients with proven N S C L C who were referred to a pulmonary consultant. In 28 of the earlier patients and 38 of the later group the cancers were completely resectable. Only 12 of the 1979-1980 group have been cured of their cancer, while 25 of the 1989-1990 are free of cancer during the less than 2-year follow-up period. It can be assumed that this number will diminish with time. Current treatment of N S C L C with surgical resection, chem o t h e r a p y , and radiotherapy has done little to improve the prognosis of lung cancer in the past 10 years. As stressed by Selikoff, the best available current method for control of lung cancer is prevention. © 1992AcademicPress, Inc.
INTRODUCTION The landmark publications of Selikoff that identify the central etiologic role of cigarette smoking and asbestos exposure are among the great contributions to the study of lung cancer (Selikoff et al., 1964, 1967, 1968). They point the way to prevention of a disease which most pulmonary physicians consider a frustrating therapeutic morass. Recently, an increasing number of publications which herald better diagnosis and treatment of lung cancer and raise the question whether Selikoff's findings aimed at prevention are of decreased relevance in 1991, have appeared. Currently, pulmonary physicians are exposed to growing numbers of publications lauding the outcome of a variety of therapies for non-small-cell carcinoma (NSCLC). Surgical cures are claimed in 60-80% of patients with stage I lesions, while combined surgery, radiotherapy, and/or chemotherapy purportedly enhance the survival of those patients whose disease cannot be resected en toto (Holmes and Gail, 1986; Martini et al., 1988; Weisenburger and Gail, 1986). Even patients with stage 1II NSCLC cancer are reported to achieve 5-year "cures" with aggressive treatments (Dillman, 1990; Mountain, 1990; Rapp et al., 1988; Skarin et al., 1989; Vokes et al., 1989). However, practicing pulmonary physicians sense that there is something amiss with these optimistic projections. Despite the numerous hopeful reports, some of which adamantly maintain that one specific therapeutic regimen is far superior to another, the physician who usually is charged with making the initial diagnosis of NSCLC and choosing the proper 1 This research was supported by The Catherine and Henry Gaisman Foundation, N e w York. 145 0013-9351/92 $5.00 Copyright© 1992by AcademicPress, Inc. All rights of reproduction in any form reserved.
146
ALVIN S. TEIRSTEIN
therapeutic regimen recognizes that very few of his/her patients achieve the same salutory outcome as those reported in the literature. Can it be that his/her surgeons, oncologists, and radiotherapists are lacking in knowledge or skill? Or are the optimistic published series the results of highly selected patients who do not reflect the broad spectrum of patients with NSCLC presenting to medical pulmonary consultants? In 1981, the author attempted to assess the prognosis for patients with NSCLC presenting in my private practice. The records of 100 consecutive patients with tissue-confirmed NSCLC who had at least a 1-year follow-up were reviewed. This was not a controlled study and roughly covered a 24-month period including 1979 and 1980. Now, to assess whether the rather dismal outcome of those patients was surpassed by current patients with NSCLC, the author has repeated the identical study, reviewing the records of another 100 consecutive patients with biopsyproven NSCLC who presented during a 14-month period including the last 2 months in 1989 and all of 1990. The shorter period of time required to amass 100 patients in the recent study reflects a progressive increase in the number of NSCLC patients seen since 1980. The 10-year follow-up data were available in 89 of the original 100 patients. The outcome of 98 patients in the recent group was available. Obviously the period of follow-up for the later cohort was less than 2 years. MATERIALS AND METHODS All patients in both groups of 100 underwent routine preoperative history, physical examination, routine blood and urine laboratory studies, electrocardiogram, chest radiograph, pulmonary function studies, and nuclear medicine bone scans. In the earlier group, 13 patients had radionuclide brain scans, 10 had gallium-67 citrate total body scans, and 9 had liver scans. In the recent group, all 100 had CT scans of the thorax extending through the adrenal glands, and 87 had brain CT scans. Presumed resectable preoperatively was defined as no evidence of intra- or extrathoracic spread of the cancer by the aggregate clinical, laboratory, and radiographic studies performed prior to surgery. Completely resectable at surgery was defined as removal of the lung cancer with no evidence of spread of the cancer to the pleura- or intrathoracic lymph nodes by operative description supported by pathologic analysis of the removed tissue. The following information was available on both groups of 100 patients: age, sex, smoking history, presumed resectability at the time of presentation, and resectability at the time of thoracotomy. In 89 patients seen 10 years ago and 98 from the recent group, data were available regarding metastatic disease presenting pre- and postoperatively, survival, and "cure." RESULTS Of the original 100 patients, 67 were men, and 53 women composed the majority of the new group. The mean age for the 10-year-old study was 62 years, while the new study revealed a mean age of 57 years. A total of 87 of the original group and 91 of the recent group were smokers or former smokers. Nine men in the original 100 and 8 men in the current 100 had a history of occupational asbestos exposure.
147
A D V A N C E S IN L U N G C A N C E R ?
Table 1 compares the resectability of the lung cancer in both groups. No attempt was made to differentiate between pneumonectomy, lobectomy, or partial lobectomy. The cancers were not grouped by cell type other than non-small-cell cancers. The patients were not compared by stage of their lung cancer, although the resectable and presumed resectable patients were almost all stage I and II and the preoperative unresectable patients were stage III or IV, in both groups. Table 1 demonstrates that after careful preoperative evaluation using the best methods available at the time, 51 of the 197%1980 follow-up and 59 of the 19891990 were thought to be potentially completely resectable prior to surgery. However, at thoracotomy, in 23 of the 51 in the original 100 patients and 21 of the 59 in the recent group, the NSCLC had extended to mediastinal lymph nodes or pleura, stage II or III carcinoma. Thus, only 28 and 38 of the 197%1980 and 1989-1990 groups, respectively, were deemed to have had their NSCLC completely resected, postoperatively. Most, but not all, patients with intrathoracic spread of their cancers were treated with postoperative radiotherapy and/or chemotherapy. Six of the 1979-1980 group underwent preoperative radiotherapy to the primary lung mass and local mediastinal metastases. One of these six is alive 10 years after successful postradiotherapy resection. None of the recent group had preoperative radiotherapy. The outcome of the completely resected NSCLCs in both groups is shown in Table 2. At this writing, 16 of the 28 patients presumed completely resected among the 1979-1980 group of patients subsequently manifested spread or a second NSCLC. Brain, liver, bone, lymph node, lung, and adrenal metastases occurred. Of the 38 complete resections in the recent group of patients 11 have already experienced intra- or extrathoracic metastatic disease and 2 have a second NSCLC during the shorter follow-up period. Thus, 12 patients seen in 1979-1980 and 27 of the 198% 1990 group potentially have been "cured" of their NSCLC. Of the early group, 72 have died, 11 from causes unrelated to their NSCLC, while 40 of the recent group have died, all but one from metastatic NSCLC. Most patients from the original study group exhibited their metastatic disease within 2 years of surgery. One died of diffuse metastatic NSCLC 8 years after resection. DISCUSSION It must be emphasized that this study of two groups of patients with NSCLC is scientifically flawed. The study is not controlled and important data are missing or unreliable. There is no comparison by stage or cell type of NSCLC. The postoperative follow-up evaluations were made by a variety of physicians with differTABLE 1 COMPARISON OF RESECTABILITY IN T w o GROUPS OF 100 PATIENTS WITH N S C L C
P r e s u m e d resectable preoperative Intrathoracic m e t a s t a s e s at surgery Inoperable preoperative Completely resectable at surgery
197%1980
198%1990
51 23 49 28
59 21 41 38
148
ALVIN S. TEIRSTEIN TABLE 2 COMPARISON OF OUTCOME OF TWO GROUPS OF 100 PATIENTS WITH NSCLC
Completely resected NSCLC Recurrence of NSCLC "Cures"
t979-1980
198%1990
28 16 12
38 13 25
ing degrees of sophistication and interest. A total of 11 of the original 100 patients and, to date, 2 of the recent 100 have been lost to follow-up. Despite these deficiencies, it is reasonable to conclude that the overall prognosis of NSCLC as demonstrated by both groups of 100 patients remains poor. One must assume that the majority of patients in the 198%1990 group who will suffer metastatic disease has yet to become apparent. Of the 38 surgical "cures," 13 have already manifested metastatic or new NSCLC and it can be expected that the remaining 25 will be reduced during the next 5 years. In comparing the two groups presenting 10 years apart, it appears that a slightly greater number of patients presumed preoperatively to be surgically curable occurred in the new study group, 59 vs 51. The number of patients with intrathoracic metastatic disease at thoracotomy was almost identical, 21 recent vs 23 in the original group. This suggests that screening patients for resectability in 1990 is perhaps more effective than the techniques available 10 years ago. However, screening techniques did not detect the 16 of 28 patients in the early group versus the somewhat better record to date of 11 of the 38 patients in the recent group, thought to have been surgically cured, who later exhibited evidence of spread of NSCLC. Approximately 90% of the patients in both groups were smokers, emphasizing the role of cigarette smoking in the etiology of NSCLC. Importantly, the majority of patients in the new study group were women. With the large number of smoking teenage females today, one can expect this percentage to climb. While these data do not constitute a scientifically valid study, it is thought that they realistically reflect the experience of the majority of medical pulmonary specialists. This study clearly shows that most patients with NSCLC are incurable at presentation to the medical pulmonary specialists and that less than 25% will survive their cancer, no matter how creatively one employs surgery, radiotherapy, and chemotherapy. Given the present state of impotence, the best treatment for NSCLC is prevention. In his landmark studies of smoking and asbestos exposure Selikoff has pointed the way. REFERENCES Dillman, R. O., Seagren, S. L., Propert, K. J., Guerra, J., Eaton, W. L., Perry, M. C., Carey, R. W., Frei, E., III, and Green, M. (1990). A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N. Engl. J. Med. 323, 940--945. Holmes, E. C., and Gail, M. (1986). The Lung Cancer Study Group. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma. J. Clin. Oncol. 4, 710715.
ADVANCES IN LUNG CANCER?
t49
Martini, N., Kris, M. G., Gralla, R. J., Bains, M. S., McCormack, P. M., and Kaiser, L. R. (1988). The effects of preoperative chemotherapy on resectability of non-smaU cell lung cancer with mediastinal lymph node metastases (N2MO). Ann. Thor. Surg. 45, 370--379. Mountain, C. F. (1990). Expanded possibilities of surgical treatment of lung cancer. Survival in stage III a disease. Chest 97, 1045-105l. Rapp, E., Pater, J. L., Wilan, A., Cormier, Y., Murray, N., Evans, W. K., Hodson, D. I., Clark, D. A., Feld, R., Arnold, A. M., Ayoub, J. I., Wilson, K. S., Latreille, J., Wierybieki, R. F., and Hill, D. P. (t988). Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. J. Clin. Oncol. 6, 633-641. Selikoff, I. J., Bader, R. A., Bader, M. E., Churg, J., and Hammond, E. (1967). Asbestos and neoplasia. Am. J. Med. 42, 487--496. Selikoff, I. J., Bader, R. A., Hammond, E. C., and Churg, J. (1968). Asbestos exposure, smoking and neoplasia. J. Am. Med. Assoc. 204, 106-112. Selikoff, I. J., Churg, J., and Hammond, E. C. (1964). Asbestos exposure and neoplasia. J. Am. Med. Assoc. 188, 22-26. Skarin, A., Jochelson, M., Sheldon, T., Malcom, A., Oliynyk, P., Overholt, R., Hunt, M., and Frei, E., III. (1989). Neoadjuvant chemotherapy in marginally resectable stage III Mo non-small cell lung cancer: Long term follow-up in 41 patients. J. Surg. Oncol. 40, 266-274. Vokes, E. E., Bitran, J. D., Hoffman, P. C., Ferguson, M. K,, Weichselbaum, R. R., and Golomb, H. M. (1989). Neoadjuvant vindesine, etoposide, and cisplatinum for locally advanced non-small cell lung cancer. Final report of a phase 2 study. Chest 96, 110-113. Weisenburger, T., and Gall, M. (1986). The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected Stage II and Stage III epidermoid carcinoma of the lung. N. Engl. J. Med. 315, 1377-1381.
Advances in Lung Cancer? 1 ALVIN S. TEIRSTEIN
Mount Sinai School of Medicine, New York 10029 and Division of Pulmonary and Critical Care Medicine, The Mount Sinai Medical Center, New York 10029 Received M a y 15, 1992 Selikoff was among the first to emphasize the etiologic role of cigarette smoking and asbestos exposure in lung cancer. Recent reports suggest that aggressive chemotherapy and radiotherapy combined with surgery have improved the prognosis in lung cancer. The outc o m e of 100 patients with non-small-cell lung cancer (NSCLC) seen in 1979-1980 was c o m p a r e d with the outcome of 100 patients seen in 1989-1990. The two groups consisted of consecutive patients with proven N S C L C who were referred to a pulmonary consultant. In 28 of the earlier patients and 38 of the later group the cancers were completely resectable. Only 12 of the 1979-1980 group have been cured of their cancer, while 25 of the 1989-1990 are free of cancer during the less than 2-year follow-up period. It can be assumed that this number will diminish with time. Current treatment of N S C L C with surgical resection, chem o t h e r a p y , and radiotherapy has done little to improve the prognosis of lung cancer in the past 10 years. As stressed by Selikoff, the best available current method for control of lung cancer is prevention. © 1992AcademicPress, Inc.
INTRODUCTION The landmark publications of Selikoff that identify the central etiologic role of cigarette smoking and asbestos exposure are among the great contributions to the study of lung cancer (Selikoff et al., 1964, 1967, 1968). They point the way to prevention of a disease which most pulmonary physicians consider a frustrating therapeutic morass. Recently, an increasing number of publications which herald better diagnosis and treatment of lung cancer and raise the question whether Selikoff's findings aimed at prevention are of decreased relevance in 1991, have appeared. Currently, pulmonary physicians are exposed to growing numbers of publications lauding the outcome of a variety of therapies for non-small-cell carcinoma (NSCLC). Surgical cures are claimed in 60-80% of patients with stage I lesions, while combined surgery, radiotherapy, and/or chemotherapy purportedly enhance the survival of those patients whose disease cannot be resected en toto (Holmes and Gail, 1986; Martini et al., 1988; Weisenburger and Gail, 1986). Even patients with stage 1II NSCLC cancer are reported to achieve 5-year "cures" with aggressive treatments (Dillman, 1990; Mountain, 1990; Rapp et al., 1988; Skarin et al., 1989; Vokes et al., 1989). However, practicing pulmonary physicians sense that there is something amiss with these optimistic projections. Despite the numerous hopeful reports, some of which adamantly maintain that one specific therapeutic regimen is far superior to another, the physician who usually is charged with making the initial diagnosis of NSCLC and choosing the proper 1 This research was supported by The Catherine and Henry Gaisman Foundation, N e w York. 145 0013-9351/92 $5.00 Copyright© 1992by AcademicPress, Inc. All rights of reproduction in any form reserved.
146
ALVIN S. TEIRSTEIN
therapeutic regimen recognizes that very few of his/her patients achieve the same salutory outcome as those reported in the literature. Can it be that his/her surgeons, oncologists, and radiotherapists are lacking in knowledge or skill? Or are the optimistic published series the results of highly selected patients who do not reflect the broad spectrum of patients with NSCLC presenting to medical pulmonary consultants? In 1981, the author attempted to assess the prognosis for patients with NSCLC presenting in my private practice. The records of 100 consecutive patients with tissue-confirmed NSCLC who had at least a 1-year follow-up were reviewed. This was not a controlled study and roughly covered a 24-month period including 1979 and 1980. Now, to assess whether the rather dismal outcome of those patients was surpassed by current patients with NSCLC, the author has repeated the identical study, reviewing the records of another 100 consecutive patients with biopsyproven NSCLC who presented during a 14-month period including the last 2 months in 1989 and all of 1990. The shorter period of time required to amass 100 patients in the recent study reflects a progressive increase in the number of NSCLC patients seen since 1980. The 10-year follow-up data were available in 89 of the original 100 patients. The outcome of 98 patients in the recent group was available. Obviously the period of follow-up for the later cohort was less than 2 years. MATERIALS AND METHODS All patients in both groups of 100 underwent routine preoperative history, physical examination, routine blood and urine laboratory studies, electrocardiogram, chest radiograph, pulmonary function studies, and nuclear medicine bone scans. In the earlier group, 13 patients had radionuclide brain scans, 10 had gallium-67 citrate total body scans, and 9 had liver scans. In the recent group, all 100 had CT scans of the thorax extending through the adrenal glands, and 87 had brain CT scans. Presumed resectable preoperatively was defined as no evidence of intra- or extrathoracic spread of the cancer by the aggregate clinical, laboratory, and radiographic studies performed prior to surgery. Completely resectable at surgery was defined as removal of the lung cancer with no evidence of spread of the cancer to the pleura- or intrathoracic lymph nodes by operative description supported by pathologic analysis of the removed tissue. The following information was available on both groups of 100 patients: age, sex, smoking history, presumed resectability at the time of presentation, and resectability at the time of thoracotomy. In 89 patients seen 10 years ago and 98 from the recent group, data were available regarding metastatic disease presenting pre- and postoperatively, survival, and "cure." RESULTS Of the original 100 patients, 67 were men, and 53 women composed the majority of the new group. The mean age for the 10-year-old study was 62 years, while the new study revealed a mean age of 57 years. A total of 87 of the original group and 91 of the recent group were smokers or former smokers. Nine men in the original 100 and 8 men in the current 100 had a history of occupational asbestos exposure.
147
A D V A N C E S IN L U N G C A N C E R ?
Table 1 compares the resectability of the lung cancer in both groups. No attempt was made to differentiate between pneumonectomy, lobectomy, or partial lobectomy. The cancers were not grouped by cell type other than non-small-cell cancers. The patients were not compared by stage of their lung cancer, although the resectable and presumed resectable patients were almost all stage I and II and the preoperative unresectable patients were stage III or IV, in both groups. Table 1 demonstrates that after careful preoperative evaluation using the best methods available at the time, 51 of the 197%1980 follow-up and 59 of the 19891990 were thought to be potentially completely resectable prior to surgery. However, at thoracotomy, in 23 of the 51 in the original 100 patients and 21 of the 59 in the recent group, the NSCLC had extended to mediastinal lymph nodes or pleura, stage II or III carcinoma. Thus, only 28 and 38 of the 197%1980 and 1989-1990 groups, respectively, were deemed to have had their NSCLC completely resected, postoperatively. Most, but not all, patients with intrathoracic spread of their cancers were treated with postoperative radiotherapy and/or chemotherapy. Six of the 1979-1980 group underwent preoperative radiotherapy to the primary lung mass and local mediastinal metastases. One of these six is alive 10 years after successful postradiotherapy resection. None of the recent group had preoperative radiotherapy. The outcome of the completely resected NSCLCs in both groups is shown in Table 2. At this writing, 16 of the 28 patients presumed completely resected among the 1979-1980 group of patients subsequently manifested spread or a second NSCLC. Brain, liver, bone, lymph node, lung, and adrenal metastases occurred. Of the 38 complete resections in the recent group of patients 11 have already experienced intra- or extrathoracic metastatic disease and 2 have a second NSCLC during the shorter follow-up period. Thus, 12 patients seen in 1979-1980 and 27 of the 198% 1990 group potentially have been "cured" of their NSCLC. Of the early group, 72 have died, 11 from causes unrelated to their NSCLC, while 40 of the recent group have died, all but one from metastatic NSCLC. Most patients from the original study group exhibited their metastatic disease within 2 years of surgery. One died of diffuse metastatic NSCLC 8 years after resection. DISCUSSION It must be emphasized that this study of two groups of patients with NSCLC is scientifically flawed. The study is not controlled and important data are missing or unreliable. There is no comparison by stage or cell type of NSCLC. The postoperative follow-up evaluations were made by a variety of physicians with differTABLE 1 COMPARISON OF RESECTABILITY IN T w o GROUPS OF 100 PATIENTS WITH N S C L C
P r e s u m e d resectable preoperative Intrathoracic m e t a s t a s e s at surgery Inoperable preoperative Completely resectable at surgery
197%1980
198%1990
51 23 49 28
59 21 41 38
148
ALVIN S. TEIRSTEIN TABLE 2 COMPARISON OF OUTCOME OF TWO GROUPS OF 100 PATIENTS WITH NSCLC
Completely resected NSCLC Recurrence of NSCLC "Cures"
t979-1980
198%1990
28 16 12
38 13 25
ing degrees of sophistication and interest. A total of 11 of the original 100 patients and, to date, 2 of the recent 100 have been lost to follow-up. Despite these deficiencies, it is reasonable to conclude that the overall prognosis of NSCLC as demonstrated by both groups of 100 patients remains poor. One must assume that the majority of patients in the 198%1990 group who will suffer metastatic disease has yet to become apparent. Of the 38 surgical "cures," 13 have already manifested metastatic or new NSCLC and it can be expected that the remaining 25 will be reduced during the next 5 years. In comparing the two groups presenting 10 years apart, it appears that a slightly greater number of patients presumed preoperatively to be surgically curable occurred in the new study group, 59 vs 51. The number of patients with intrathoracic metastatic disease at thoracotomy was almost identical, 21 recent vs 23 in the original group. This suggests that screening patients for resectability in 1990 is perhaps more effective than the techniques available 10 years ago. However, screening techniques did not detect the 16 of 28 patients in the early group versus the somewhat better record to date of 11 of the 38 patients in the recent group, thought to have been surgically cured, who later exhibited evidence of spread of NSCLC. Approximately 90% of the patients in both groups were smokers, emphasizing the role of cigarette smoking in the etiology of NSCLC. Importantly, the majority of patients in the new study group were women. With the large number of smoking teenage females today, one can expect this percentage to climb. While these data do not constitute a scientifically valid study, it is thought that they realistically reflect the experience of the majority of medical pulmonary specialists. This study clearly shows that most patients with NSCLC are incurable at presentation to the medical pulmonary specialists and that less than 25% will survive their cancer, no matter how creatively one employs surgery, radiotherapy, and chemotherapy. Given the present state of impotence, the best treatment for NSCLC is prevention. In his landmark studies of smoking and asbestos exposure Selikoff has pointed the way. REFERENCES Dillman, R. O., Seagren, S. L., Propert, K. J., Guerra, J., Eaton, W. L., Perry, M. C., Carey, R. W., Frei, E., III, and Green, M. (1990). A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N. Engl. J. Med. 323, 940--945. Holmes, E. C., and Gail, M. (1986). The Lung Cancer Study Group. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma. J. Clin. Oncol. 4, 710715.
ADVANCES IN LUNG CANCER?
t49
Martini, N., Kris, M. G., Gralla, R. J., Bains, M. S., McCormack, P. M., and Kaiser, L. R. (1988). The effects of preoperative chemotherapy on resectability of non-smaU cell lung cancer with mediastinal lymph node metastases (N2MO). Ann. Thor. Surg. 45, 370--379. Mountain, C. F. (1990). Expanded possibilities of surgical treatment of lung cancer. Survival in stage III a disease. Chest 97, 1045-105l. Rapp, E., Pater, J. L., Wilan, A., Cormier, Y., Murray, N., Evans, W. K., Hodson, D. I., Clark, D. A., Feld, R., Arnold, A. M., Ayoub, J. I., Wilson, K. S., Latreille, J., Wierybieki, R. F., and Hill, D. P. (t988). Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. J. Clin. Oncol. 6, 633-641. Selikoff, I. J., Bader, R. A., Bader, M. E., Churg, J., and Hammond, E. (1967). Asbestos and neoplasia. Am. J. Med. 42, 487--496. Selikoff, I. J., Bader, R. A., Hammond, E. C., and Churg, J. (1968). Asbestos exposure, smoking and neoplasia. J. Am. Med. Assoc. 204, 106-112. Selikoff, I. J., Churg, J., and Hammond, E. C. (1964). Asbestos exposure and neoplasia. J. Am. Med. Assoc. 188, 22-26. Skarin, A., Jochelson, M., Sheldon, T., Malcom, A., Oliynyk, P., Overholt, R., Hunt, M., and Frei, E., III. (1989). Neoadjuvant chemotherapy in marginally resectable stage III Mo non-small cell lung cancer: Long term follow-up in 41 patients. J. Surg. Oncol. 40, 266-274. Vokes, E. E., Bitran, J. D., Hoffman, P. C., Ferguson, M. K,, Weichselbaum, R. R., and Golomb, H. M. (1989). Neoadjuvant vindesine, etoposide, and cisplatinum for locally advanced non-small cell lung cancer. Final report of a phase 2 study. Chest 96, 110-113. Weisenburger, T., and Gall, M. (1986). The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected Stage II and Stage III epidermoid carcinoma of the lung. N. Engl. J. Med. 315, 1377-1381.
