Carcinoma of the Lung

THE ANNALS OF THORACIC SURGERY Journal of The Society of Thoracic Surgeons and the Southern Thoracic Surgical Association VOLUME 1 I - NUMBER 3 0 MARCH 1971 Carcinoma of the Lung M. L. Dillon, M.D., and R. W. Postlethwait, M.D. ABSTRACT A review of 1,064 patients entered into the tumor registry of the Durham Veterans Administration Hospital from January, 1953, through December, 1969, is reported. The 566 patients who were entered between January, 1953, and December, 1964, constitute a group in which survival for five or more years could be studied, and they are reported in more detail. Nineteen patients survived five or more years; of these, 11 had coin lesions less than 4 cm. in diameter and 3 had small lesions with poorly demarcated margins. The small lesions combined with the absence of extension into the lymph nodes and pleura in the survivors make it appear that anatomical localization is the most important factor in long-range survival. The recent increasing use and greater reliability of cytological diagnostic procedures neither increased the percent of patients judged capable of benefiting from resection nor reduced the percent of patients having thoracotomy and biopsy without resection. The number of cases of primary carcinoma of the lung has continued to increase yearly. E ffective therapy for carcinoma of the lung was initiated in 1933, when Graham and Singer [3] did the first pneumonectomy for this disease. At the present time, total removal of a lung cancer offers the best chance for cure. The ability of physicians to identify the carcinoma while total excision is still possible has not improved, however. In addition, the incidence of carcinoma of the lung has increased yearly; among men in the United States today it is the malignancy that most frequently causes death. Periodic analysis of the clinical experience with lung carcinoma is important to determine the scope of the problem and to define further those factors which influence survival and management. From the Department of Thoracic and Cardiovascular Surgery, \'eterans Administration Hospital, Durham, N.C. Presented at the Seventeenth Annual Meeting of the Southern Thoracic Surgical Association, Bermuda, Nov. 5-7, 1970. Address reprint requests to Dr. Dillon, Vrterans Administration Hospital, Fulton St. and Erwin Rd., Durham, N.C. 27705. VOL. 1 1, NO. 3, MARCH, '971 193

DILLON AND POSTLETHWAIT I 40 - A NUMBER MEW PATIENTS I 30- X RESECTIONS 53 55 57 59 61 63 65 67 C Year FIG. 1. The number of new batients with carcinoma of the lung has increased each year (top line) with no ap$reciable change in the percentage 6f patients who have had resectable lesions (bottom line). 3 CLINICAL MATERIAL A review was made of 1,064 patients with carcino:ma of the lung who were entered into the tumor registry of the Durham Veterans Administration Hospital between January 1, 1953, and December 31, 1969. In January, 1970, 103 patients (9.7%) were still living and 958 (90.5%) had died; of these, 952 had carcinoma and 6 had no carcinoma at the time of death. Three patients were lost to followup; bronchial adenomas were not included in this review. Only 2 patients were women. Of the 1,064 patients 172 (16%) underwent resection. The number of new patients entered into the tumor registry has increased more than twelvefold in sixteen years: 11 patients were entered in 1953 and 134 patients in 1969. NO appreciable increase has occurred in the percentage of patients who have had resectable lesions. Resectability has ranged between 7 and 25% throughout the period reviewed (Fig. 1). IRRADIATION AND CHEMOTHERAPY To determine the effect of chemotherapy and irradiation, the treatment of 632 patients who had died was studied. Of these, 238 had no therapy, 107 received chemotherapy, 2 15 received irradiation, and 72 received chemotherapy and irradiation. The 50% survival time was less than 1 month for those who received no therapy, 2.5 months for those who received chemotherapy, 3.5 months for those who received irradiation, and 4.8 months for those who received chemotherapy and irradiation. The beneficial effect of irradiation and chemotherapy over a period of 12 months is illustrated in Figure 2. The average survival time for the 238 patients who received no therapy was 2.45 months. Although none of the survivors who lived five or more years following resection had received radiation therapy, 2 patients who had undergone thoracotomy without resection followed by irradiation were exceptional in that they both survived eight years. 194 THE ANNALS OF THORACIC SURGERY

Carcinoma of the Lung 0 No therapy-236 potients 8 Chemotherapy -lolpatients A Irradiation -2lSpatients Chemotherapy and Irradiation - I 2 3 4 5 6 7 8 9 1 0 1 1 1 2 Months alter Diagnosis FIG. 2. Szcrviual in 632 patients with carcinoma of the lung. Irradiation or chemotherapy alone or combined had a beneficial palliative eflect over a 12- month period as compared to patients who received no therapy. 566 PATIENTS-FIVE OR MORE YEARS' FOLLO kv-up From January, 1953, through December, 1964, 566 patients were admitted with cancer of the lung. There were 19 five-year survivors (3.4%). Of these 566 atients, 358 had no thoracotomy, 110 had thoracotomy without resection, and &3 had thoracotomy with resection. Three patients underwent segmental resection, 50 had lobectomy, and 45 had pneumonectomy. METHODS OF DIAGNOSIS The method of diagnosis for 358 patients who had no thoracotomy is listed in Table 1. Of the 70 patients diagnosed at postmortem examination, only 8 had not been suspected before death of having lung cancer. All 8 had small, asymptomatic lesions without metastasis. The 22 needle biopsies of the lung were performed during a clinical study to evaluate this procedure. That there was cytological diagnosis in only 13 (3.7%) of the 358 patients who did not have thoracotomy is a reflection of the lack of local interest in and availability of cytological procedures during this period. In contrast, during the year 1969, 22 of 77 patients (29%) who did not have thoracotomy had the diagnosis established by cytology; 6 others showed atypical cells, and 15 had negative results. There were 34 patients whose diagnosis was based only on the clinical history, physical examination, and roentgenographic examination. A few of these patients had refused diagnostic procedures, and such procedures were not advised for the remaining patients because of markedly impaired cardiorespiratory function or faradvanced metastatic disease. Of the 45 patients who had pneumonectomy prior to December 31, 1964, 25% were diagnosed by bronchoscopy. This percentage remained the same for the year 1969 (2 of 9 undergoing pneumonectomy). Cytological diagnosis in the

DILLON AND POSTLETHWAIT TABLE 1. METHOD OF DIAGNOSIS IN 358 PATIENTS WITHOUT THORACOTOMY Method No. of Patients Lymph node biopsy 81 Bronchoscopy 74 Autopsy Bone biopsy Needle biopsy Cytology Liver biopsy Brain biopsy Spinal cord biopsy Soft tissue biopsy Clinical findings pneumonectomy patients before December 31, 1964, was only 2% as contrasted with 33% for those undergoing pneumonectomy in 1969. Although 2 of the 50 patients receiving lobectomy before December 31, 1964, were diagnosed by bronchoscopy, all of the 18 patients during the year 1969 required resection for diagnosis. Cytological specimens were obtained for 8 of the 18 patients who had lobectomy in 1969, and all were negative. FIVE-YEAR SURVIVORS Of the 19 five-year survivors, 17 had undergone resection. Six of these patients had had pneumonectomy and ll, lobectomy. The other 2 patients, who had had thoracotomy and biopsy, were found to have nonresectable lesions because of tumor invasion into the pleura. Both received irradiation, both survived eight years, and both died with evidence of extension of their disease although the immediate cause of death was not cancer. Very localized disease was present in 14 of the 17 patients who had had their tumor resected. Eleven had coin lesions less than 4 cm. in diameter, and 3 had small lesions with poorly defined margins. Of the 566 patients 98 underwent resection, but only 59 tumors were removed with hope of cure. Among these 59 patients no invasion of pleura occurred and no involved lymph nodes remained following resection. The fiveyear survival rate for patients whose tumors were resected for cure was 29%. TREATMENT AND RESULTS Pneumonectomy for Palliation. Of 45 pneumonectomies, 22 were done for palliation in patients who had invasion into the pleura or in whom involved lymph nodes remained. All 22 patients were dead within one year. (Two additional patients died of hemorrhage from the pulmonary artery during attempted pneumonectomy as palliation for carcinoma of the lung; they are included in Table 3 to reflect the operative mortality more accurately.) The operative mortality with pneumonectomy for palliation was 5 of 24 patients (21%). Two patients bled from the pulmonary artery at operation, 1 bled from the pulmonary vein 1 day after operation, and 2 died of inadequate cardiopulmonary function 3 days and 5 days, respectively, following pneumonectomy with resection of a large portion of the chest wall (Table 2). Pneumonectomy for Cure. There were 23 patients who had pneumonectomy for cure. Six survived five or more years, resulting in a 26% five-year survival after pneumonectomy for cure. Four of these 6 were described as having coin lesions at the time of resection. Of the 6 five-year survivors, 1 committed suicide five years and seven months after operation. The other 5 are living as follows: 1 at seventeen years, 2 at ten years, 1 at eight years, and 1 at seven years after operation. Of the 17 patients who lived less than five years, 2 lived four years, 2 lived three 70 36 22 13 9 8 7 4 34 196 THE ANNALS OF THORACIC SURGERY

Carcinoma of the Lung TABLE 2. MORTALITY IN 47 PATIENTS WHO UNDERWENT PNEUMONECTOMY No. of Postoperative Cause of Death Patients Days Myocardial infarction Intraoperative bleeding Cardiopulmonary insufficiency Postoperative bleeding from pulmonary vein Total 6 (13%) 14 3 and 5 2 years, 3 lived two years, 6 lived one year, and 4 lived less than one year. There was 1 death from a myocardial infarction 14 days after operation. The operative mortality with pneumonectomy for cure was 4%. Seven of the 17 patients who died less than five years following pneumonectomy for cure were examined postmortem. In 3 patients recurrent carcinoma was found only in the bronchial stump, causing respiratory insufficiency in the remaining lung. All 3 had squamous cell carcinoma. The 1 patient who died of acute myocardial infarction 14 days after operation had squamous cell carcinoma in the operative specimen at the line of resection. However, no residual tumor was found at postmortem examination, but squamous cell metaplasia of the bronchial stump was present. The remaining 15 deaths were due to recurrent carcinoma of the lung. Lobectomy for Palliation. Of the 50 lobectomies performed, 14 were for palliation. Eleven patients were dead within one year, and all 14 were dead within three years. Lobectomy for Cure. Thirty-six lobectomies were done for cure. Eleven patients lived for five or more years, of whom 6 had coin lesions less than 4 cm. in diameter and 3 had lesions that were seen by roentgenogram as small with poorly defined margins. The five-year survival rate with lobectomy for cure was 31%. Of the 11 fiveyear survivors, 5 have since died. One of these patients, who initially had a squamous cell carcinoma, died seven years after operation. Death was due to complications of encephalopathy from cerebral arteriosclerosis, and a new, asymptomatic oat cell carcinoma of the lung was found at postmortem examination. Another patient who initially had a squamous cell carcinoma died of pneumonia five years after operation and was found to have an asymptomatic adenocarcinoma of the lung. Two patients died of metastasis of squamous cell carcinoma at eight years, and 1 patient died of metastatic undifferentiated carcinoma at nine years. One patient who had an alveolar cell carcinoma died of an acute myocardial infarction ten years following operation. The others are living as follows: 1 at fourteen years, 1 at twelve years, 2 at eleven years, 1 at ten years, and 1 at six years. One elderly, debilitated patient was lost to follow-up one year after operation. Of the 24 patients who lived less than five years, 1 lived four years, 4 lived three years, and 19 lived less than three years. The postoperative mortality for lobectomy was 2%, as 1 patient died of an acute myocardial infarction 3 days after operation. AVERAGE SURVIVAL Average survival time was determined for several groups of patients who have died of their disease; the patients still living and the patients whose deaths were related to operation are excluded. These data are presented in Table 3 to show the effect on survival time of the various procedures, even though cure may not have been attained. VOL. 11, NO. 3, MARCH, 1971 197

DILLON AND POSTLETHWAIT TABLE 3. AVERAGE SURVIVAL TIME OF PATIENTS WHO DIED OF LUNG CANCER Average No. of Survival Procedure Patients (mo.) Thoracotomy & biopsy 106 8.0 Pneumonectomy for palliation 19 5.7 Pneumonectomy for cure 17 26.5 Lobectomy for palliation 14 11.0 Lobectomy for cure 29 31.0 CELL TYPE The distribution of cell types is within the ranges established for larger and collected series. In our pneumonectomy group, 60% had squamous cell carcinoma, 17% undifferentiated carcinoma, and 11% adenocarcinoma; the type was not specified for 11%. This is in contrast to the distribution in those patients who were diagnosed by biopsy of distant metastases, of whom 18% had squamous cell carcinoma, 50% had undifferentiated carcinoma, 21% had adenocarcinoma, and 11% had cancer of unspecified type. All three cell types were represented in the 19 five-year survivors. COMMENT The incidence of carcinoma of the lung is increasing yearly without an increase in the percentage of resectable tumors. It is now the most common malignant lesion seen at our hospital. Irradiation and chemotherapy were not used in any of the patients who survived longer than five years following resection. Two patient!; survived eight years following thoracotomy and biopsy for nonresectable lesions; they had received irradiation. They are the exception to the rule that patients with nonresectable carcinoma of the lung do not survive more than four years. Irradiation and chemotherapy were demonstrated to increase length of survival at all times during a 12-month period. Patients surviving for more than five years characteristically had lesions that were relatively localized anatomically, either in the periphery or in the major bronchial divisions, and that were free of pleural or regional lymph node extension. These findings are similar to those of Gobbel, Sawyers, and Rhea [Z]. This is further emphasized by the findings that 11 of the 19 five-year survivors had coin lesions less than 4 cm. in diameter and that 3 additional patients had small lesions with poorly demarcated margins as seen on chest roentgenograms. An aggressive attitude toward resection of these lesions, as advocated by Steele and his associates [5], seems reasonable. Collier and his co-workers [I] have demonstrated that vascular invasion is the most important criterion affecting prognosis. Unfortunately such invasion is frequent, occurring even with small lesions. This is emphasized by the finding of brain and bone metastases as pre- 198 THE ANNALS OF THORACIC SURGERY

Carcinoma of the Lung senting symptoms in 5 patients with coin lesions during the year 1969. One was squamous cell carcinoma, 3 were adenocarcinoma, and 1 was undifferentiated carcinoma. The usual distribution of cell types is altered among selected groups of patients by the tendency of squamous cell carcinoma to involve major bronchi, for adenocarcinoma to be peripheral, and for undifferentiated carcinoma to metastasize in the bloodstream. Three of 7 patients who died following pneumonectomy for squamous cell carcinoma were found at postmortem examination to have recurrence only in the bronchial stump. This confirms the observation of Griess, McDonald, and Clagett [4] that this type of recurrence was more frequent with squamous cell carcinoma. Aggressive use of pneumonectomy for palliation was associated with a mortality of 21%, and all deaths were related to the operative procedure. This is inordinately high when contrasted with a mortality of 4% with pneumonectomy for cure. The futility of palliative pneumonectomy is emphasized by the findings that none of the 24 patients so treated lived more than one year and that the average survival, excluding operative mortality, was less than 6 months. On the other hand, palliative lobectomy did not increase postoperative mortality, but neither did it greatly increase the average survival time. It is more meaningful to compare the average survival of patients who underwent resection with the survival of those having thoracotomy and biopsy, rather than with the survival in a group of terminal patients who received no treatment (see Table 3). Many of the 238 patients represented in the survival curve in Figure 2 fit this category of having terminal cancer and had an average survival of only 2.45 months. The dismal survival rate during the past four years is not significantly different from that of the previous nine years. Both the increased use of cytology within the past year and improvement in cytological methods of diagnosis have resulted in greater numbers of diagnoses by this method. However, in our patients the greater role of cytology in diagnosis is not reflected in an increase in the percent of patients considered candidates for resection, which has ranged between 7 and 25% over a sixteen-year period; nor has increased use of cytological diagnosis been reflected in a decrease in the percent of patients having thoracotomy and biopsy without resection (19.5% for the years 1953-1964 as compared to 20.9% for the year 1969). REFERENCES 1. Collier, F. C., Enterline, H. T., Kyle, R. H., Tristan, T. T., and Greening, R. The prognostic implications of vascular invasion in primary carcinomas of the lung. A.M.A. Arch. Path. 66~594, 1959. 2. Gobbel, W. G., Sawyers, J. L., and Rhea, W. G. Experience with palliative VOL. 11, NO. 3, MARCH, 1971 199

DILLON AND POSTLETHWAIT resection and irradiation therapy for carcinoma of the lung. J. Thorac. Cardiovasc. Surg. 53:183, 1967. 3. Graham, E. A., and Singer, J. J. Successful removal of an entire lung for carcinoma of the bronchus. J.A.M.A. 101:1371, 1933. 4. Griess, D. F., McDonald, J. R., and Clagett, 0. T. The proximal extension of carcinoma of the lung in the bronchial wall. J. Thorac. Surg. 14:362, 1945. 5. Steele, J. D., Kleitsch, W. P., Dunn, J. E., Jr., and Buell, P. Survival in males with bronchogenic carcinomas resected as asymptomatic solitary pulmonary nodules. Ann. Thorac. Surg. 2:368, 1966. NOTICE FROM THE AMERICAN BOARD OF THORACIC SURGERY The 1971 fall examinations will be given as follows: Written Examination. To be held at various centers throughout the country on September 10, 1971. Final date for filing applications is June 1, 1971. Oral Examination. To be given Oct. 23-24, 1971, in New York, N.Y. Final date for filing applications is June 1, 1971. The registration fee is $50 and the examination fee is $250. Please address all communications to the American Board of Thoracic Surgery, Inc., 14624 East Seven Mile Road, Detroit, Mich. 48205. 200 THE ANNALS OF THORACIC SURGERY