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Surgical therapy of lung cancer
Surgical therapy of lung cancer A total of 1,615 patients with a confirmed diagnosis of lung cancer were treated at Roswell Park Memorial Institute between 1963 and 1974. Particular emphasis was given in this review to the 295 patients that underwent surgical resection of their primary lung lesion. Factors such as histology, type of resection, sex, age, staging, and degree of dissemination were considered possible influences on survival. The risks and benefits of intentional reductive or palliative surgery are considered along with the risk related to thoracotomies performed for diagnostic purposes. Ronald G. Vincent, M.D., Hiroshi Takita, M.D., Warren W. Lane, Ph.D., Alberto C. Gutierrez, M.D., and John W. Pickren, M.D., Buffalo, N. Y.
J. he first successful pneumonectomy for cancer of the lung was performed by Graham and Singer13 in 1933. Since 1933 both the incidence of and the deaths from lung cancer have increased more than 20-fold in men, and have increased steadily among women, but to a lesser degree. Surgery has been established as the form of therapy in which cure might best be anticipated under circumstances where a preoperative assessment has accurately established the presence of limited primary disease.5' 8' n ' 12, 22, 33 The therapeutic limitations of surgery are also now well recognized, and future progress in preventing or controlling this disease is contingent upon finding methods which will either supplant or enhance the therapeutic effectiveness of surgery. 2,4 - 7 The purpose of this study is to assess the factors of histology, sex, stage, age, tumor location, and types of surgical procedures as they relate to the possible curative resection of lung cancer. Materials and methods At Roswell Park Memorial Institute, between the years of 1963 and 1974, 1,615 patients were treated with a histologically established diagnosis of primary lung cancer. Roswell Park Memorial Institute is maintained solely for the benefit of cancer patients. For this reason, the From the Roswell Park Memorial Institute, Buffalo N. Y. Supported in part by NCI Contract N01-CM-33734. Received for publication Aug. 6, 1975. Address for reprints: Ronald G. Vincent, M.D., Chief of Thoracic Surgery, Roswell Park Memorial Institute, Buffalo, N. Y.
patient population may be somewhat different from that of a community hospital.3 A total of 567 (35.1 per cent) of these patients were surgically explored; 295 (18.3 per cent) received surgical resection of their lung lesion and 272 (16.8 per cent) had a diagnostic thoracotomy with biopsy but without resection. All surgically excised lung specimens were examined further to ascertain the presence of lymph nodes, and the number and location of nodes involved by cancer were recorded. Histological confirmation of suspected mediastinal nodes was obtained and recorded along with the documentation of direct tumor invasion of the mediastinum or chest wall. All patients were "clinically" staged according to the methods established by the American Joint Committee on Staging and End Results Reporting and all surgical patients were staged again following surgery by the same methods (Table I). Eleven patients were lost to follow-up and for statistical purposes are presumed to be dead. The autopsy rate at Roswell Park Memorial Institute is 95 per cent of all patients who die on the premises. Deaths that occurred within 30 days of surgery are considered operative deaths and these patients are included in all of the statistical assessments that follow. Survival is based on the Cutler and Ederer9 life table method. A wedge or segmental resection was usually performed under those circumstances where the patient's pulmonary reserve was compromised to the degree that resection of large amounts of lung tissue was not deemed wise. A radical pneumonectomy is defined as a surgical procedure which requires removal 5 81
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Table I. Work sheet for staging lung cancer No.: Name: Directions: Encircle the T, N, and M rating following the description that is most accurate for the patient's cancer. Encircle the value for each rating and add to obtain the total value. Consult the table at the bottom of the form to determine the stage . . . If patient had a thoracotomy, the surgical evaluative (postthoracotomy) classification may be entered on this same form. Similarly, if patient had a resection, the postsurgical treatment classification may be entered on this form. Classification Surgical evaluative value
Clinical value Primary tumor—T No evidence of primary tumor Tumor proved by the presence of malignant cells in secretions but not visualized roentgenographically or bronchoscopically A tumor that is 3.0 cm. or less in greatest diameter, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy A tumor more than 3.0 cm. in greatest diameter or a tumor of any size which, with its associated atelectasis or obstructive pneumonitis, extends to the hilar region. At bronchoscopy the proximal extent of demonstrable tumor must be at least 2.0 cm. distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung and there must be no pleural effusion A tumor of any size with direct extension into an adjacent structure such as the chest wall, the diaphragm, or the mediastinum and its contents; or demonstrable bronchoscopically to be less than 2.0 cm. distal to the carina; or any tumor associated with atelectasis or obstructive pneumonitis of an entire lung or a pleural effusion Regional lymph nodes—N: No demonstrable spread to regional lymph nodes Spread to lymph nodes in the ipsilateral hilar region Spread to lymph nodes in the mediastinum Distant metastasis—M: No distant metastasis Distant metastasis such as in scalene, cervical, or contralateral hilar lymph nodes, brain, lung, liver, etc. Total value 0 1 or 2 3 4 or more
Stage Occult carcinoma I II III
TO TX
0 0
TO TX
Postsurg. treatment value 0 0
TO TX
Tl
Tl
Tl
T2
T2
T2
T3
T3
4
T3
0 0
NO Nl N2
0 1 4
NO Nl N2
0 1 4
NO Nl N2
0 1 4
MO Ml
0 4
MO Ml
0 4
MO Ml
0 4
T N M Stage
Summary of staging T T N N M M Stage Stage
Cell type: squamous, □; small, □; adenocarcinoma, □; large, Q; unknown, □. If patient had a resection, indicate whether postsurgical treatment classification was based on pathological evaluation of: Primary tumor mass □ yes D no □ unknown Regional lymph nodes □ yes D no □ unknown Distant sites □ yes D no □ unknown
of direct tumor extension to the mediastinum, pericardium, diaphragm, or chest wall. Results Type of surgery. The median survival time of the 295 patients who underwent a definitive surgical
resection was 17.5 months, with a 5 year survival of 17.3 per cent. Included in these 295 patients were 67 patients in whom an incomplete resection or intentional palliative resection was performed. In these 67 cases invasion of the chest wall, mediastinum, or bronchus caused the surgeon to doubt that there had been a total
Volume 71 Number 4 April, 1976
Surgical therapy of lung cancer
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WEDGE/SEQ. LOBECTOMY PNEUMONECTOMY RAD. PNEUMONECTOMY
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TIME IN MONTHS Fig. 1. Survival by type of surgical resection for lung cancer (N = 295). Table II. Postoperative mortality and survival rates for lung cancer* Surgical therapy Wedge or Segmental Lobectomy Pneumonectomy Radical pneumonectomy Total resections Thoracotomy without resection Palliative or reductive
No.
Per cent of total
30 day mortality rate
<%)
Median survival (mo.)
5 yr. survival
10 yr. survival
<%)
(%)
>47t
==66.7t
< 66.7t
4
1.4
0
160 101 30
54.2 34.2 10.2
1.9 11.9 20.0
24.1 11.2 5.9
20.1 15.3 0
20.1 8.0 0
295
100
7.1
17.5
17.3
13.3
272
100
4.1
6.0
0.6
s0.6t
67
100
6.0
11.6
6.3
<6.3t
*Chi square = 21.5; DF = 3; P < 0.001 (omitting wedge/segmental). tTime not reached.
ablation of the tumor by the surgical resection of the lung. Usually the presence of residual disease was verified by histological examination. Since the possibility of viable residual disease was evident to the surgeon, additional therapy, such as radiotherapy, was frequently instituted. These 67 patients had an operative mortality rate of 6.0 per cent, a median survival rate of 11.6 months, and a 6.3 per cent 5 year survival (Table II).
The survival data also show an operative mortality rate of 1.9 per cent for lobectomies, 11.9 per cent for pneumonectomies, and 20 per cent for radical pneumonectomies, with an over-all operative mortality rate of 7.1 per cent for all resected cases. The operative mortality rate, the median survival rate and the per cent of 5 and 10 year survival0 ~.s they relate to the types of surgery performed are all given in Table II. As the magnitude of surgery required for the resection of the
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N=I6I N = I6 N=I7 N = 72 N = I8 N=M
40
60
80
100
120
TIME IN MONTHS Fig. 2. Survival by histologic cell type following surgical resection of lung cancer (N = 295). Table III. Postoperative mortality and survival rates for lung cancer: Surgical resections by histology*
Cell type
No.
Per cent of total
Squamous Adeno Large Small Bronchoalveolar Undifferentiated Total
161 72 17 16 18 11 295
54.6 24.4 5.8 5.4 6.1 3.7 100
30 day mortality rate {%)
Median survival (mo.)
Syr. survival
(%)
<%)
5.0 8.4 5.9 25.0 11.1 9.1 7.1
19.3 23.2 10.0 5.5 24.4 18.5 17.5
19.9 11.4 20.9 0 18.2 18.2 17.3
15.3 0 20.9 0 18.2 S18.2t 13.3
10 yr. survival
*Chi square = 12.1; DF ■■5; P < 0.05. tTime not reached.
tumor increased, the operative mortality rate increased, and the median and 5 year survival rates decreased (Fig. 1). The value of intentional reductive surgery or palliative surgery must be considered in view of experience where thoracotomy is performed but a resection is not achieved. There were 272 patients at this Institution between 1963 and 1974 who had a diagnostic thoracotomy but without resection. The operative mortality rate was 4.1 per cent, with a median survival of 6.0 months and a 5 year survival of 0.6 per cent (Table II). Histology. During the period between 1963 and
1974 the histological findings of the tumors of 1,615 patients treated for lung cancer were distributed by cell type as follows: squamous cell, 39.6 per cent; adenocarcinoma, 23.2 per cent; small cell, 18.4 per cent, large cell, 8.6 per cent; bronchioalveolar, 2.8 per cent; and undifferentiated, 7.4 per cent. Of all the lung tumors that were resected, 161 were squamous-cell carcinoma and only 16 (5.4 per cent) were small-cell carcinoma, suggesting that a squamous-cell carcinoma is the cell type most amenable to surgical resection and that small-cell carcinoma is rarely resected successfully. The operative mortality rate as well as the median and 5 year survival rates for
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Surgical therapy of lung cancer
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lOOr MALE FEMALE
40
60
N = 247 N = 48
80
120
TIME IN MONTHS Fig. 3. Survival by sex following surgical resection of lung cancer (N = 295, p > 0.05). Male median survival 16.1 months; female median survival 23.1 months. these two cell types would also tend to substantiate this observation (Table III). In the 295 patients who had a pulmonary resection of their lung cancer, no significant difference can be noted in the survival of the resected patient with regard to tumor histology, although small-cell carcinoma has a uniformly poor prognosis (Fig.2). Sex. During the period of this study, the incidence of lung cancer among females has doubled. In 1963 at Roswell Park Memorial Institute the ratio of men to women treated for lung cancer was 9 : 1 . Each year subsequently the incidence of lung cancer among women increased until 1974, when the ratio of men to women became 4 : 1 . Women also had a greater incidence of adenocarcinoma (34 per cent) and small-cell carcinoma (26 per cent) than did men. These facts, however, did not significantly influence the operative mortality rate or the over-all survival rate which is essentially the same as it is with men (Fig. 3). Age at diagnosis. The decision to perform major surgery on a patient who is deemed resectable but is over 70 years of age is usually made with great restraint. There may also be a tendency to be more aggressive in performing surgery in younger patients. We found the operative mortality and median survival rates to be essentially the same in all patients between 40 and 70 years of age who were selected for resection.
Table IV. Postoperative mortality and survival rates for lung cancer: Surgical resections by age*
Age (yr.)
No.
20-40 8 40-49 46 50-59 95 60-69 106 70+ 40 Total 295
Per cent of total 2.7 15.6 32.2 35.9 13.6 100
30 day 5 yr. mortality Median survival survival rate <%) (mo.) (%) 12.5 4.4 7.4 8.5 7.5 7.1
14.1 18.6 16.8 19.4 14.2 17.5
0 20.3 21.5 15.9 7.8 17.3
10 yr. survival
<%) 0 20.3 14.4 11.3 <7.8t 13.3
*Chi square = 3.9 DF = 4; P > 0.05. fTime not reached.
However, the percentage of 5 year and 10 year survival is reduced among patients who were treated and were over 70 or under 40 years of age at the time of diagnosis (Table IV). The median age at the time of surgery was 60.7 for men and 53.3 for women. Stage of disease. All patients in this study were "clinically" and "surgically" staged according to the methods adopted by the American Joint Committee on Staging and End Results Reporting (Table I). Those patients who demonstrated no evidence of metastasis or dissemination (Stage I) had a significantly better survival than those patients with either ipsilateral
5 86
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80
o z
> > rr
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STAGE I STAGE H STAGE M
lA
A
N=I38 N= 58 N= 99
60
40 -
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20
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60
80
1
100
1
120
TIME IN MONTHS Fig. 4. Survival by stage following surgical resection of lung cancer (N = 295).
Table V. Postoperative mortality and survival rates for lung cancer: Surgical resections by stage*
Stage No. I II III Total
138 58 99 295
Per cent of total 46.8 19.7 33.5 100
30 day mortality rate
<%) 5.1 6.9 10.2 7.1
Median survival (mo.)
5 yr. survival
10 yr. survival
<%)
(%)
26.7 14.7 8.0 17.5
28.8 6.9 6.9 17.3
23.3 S3.5t s6.9t 13.3
*Chi square = 31.3; DF = 2 P < 0.001. tTime not rea:hed.
hilar node metastasis (Stage II) or those with distant metastasis and/or direct extension into adjacent structures (Stage III) (Fig. 4). P < 0.001.* The operative mortality rate was increased and the median survival rate decreased in resected Stage III disease (Table V). Lymph node involvement. With each surgical resection, suspicious nodes in the mediastinum were biopsied and, where feasible, were removed with the surgical specimen. Each lung removed at surgery was examined for the presence of nodes and, where found, *The Breslow Test is used for all assessments of statistical significance.6
their location and pathology, if any, were noted. Of the 295 patients that underwent surgical resection, 183 (62 per cent) were felt not to have had metastasis to lymph nodes at the time of surgery. The median survival of this group was 21.2 months, with a 5 year survival of 24.8 per cent (Table VI). The ages of patients found with positive lymph nodes at the time of surgery are listed by cell type as follows: squamous, 35 per cent; adenocarcinoma, 44 per cent; large-cell carcinoma, 47 per cent; small-cell carcinoma, 38 per cent. Where metastatic nodes were found at surgery, median survival became less than 14.1 months. A 5 year survival of 24.8 per cent was achieved when no metastatic nodes were evident at the time of surgery but if nodes were evident there were no 5 year survivors. We were unable to detect any prognostic distinction between the metastatic involvement of hilar nodes and the metastatic involvement of mediastinal nodes. (Fig. 5). This would suggest to us that once a tumor has demonstrated a propensity for dissemination, it rarely limits this capacity to the immediate vicinity of the primary tumor. Autopsies. Autopsies were performed on 34.6 per cent of the 295 patients who had surgical resection of their lung lesion. Eighteen (17.6 per cent) of these patients had no evidence of residual tumor at the time of death.
Volume 71 Number 4 April, 1976
Surgical therapy of lung cancer
80 o z > >
rr 3
l \ 'jl
^
60 -
NONE HILAR MEDIASTINAL
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N=I83 N = 60 N = 52
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TIME IN MONTHS Fig. 5. Survival by metastatic node involvement following surgical resection of lung cancer (N
295).
Table VI. Postoperative mortality and survival rates for lung cancer: Surgical resections by node metastasis*
Metastatic lymph nodes No nodes Hilar nodes only Mediastinal nodes Total
30 day mortality rate
5 yr. survival
10 yr. survival
(%)
Median survival (mo.)
(%)
(%)
No.
Per cent of total
183 60
62.0 20.4
6.6 5.0
21.2 13.3
24.8 0
20.5 0
52
17.6
11.5
14.1
4.3
0
295
loo"
~1~A
Tr?
~H3
13.3
•Chi square = 7.3; DF = 2; P < 0.05.
Of particular interest were the autopsies performed on 32 of the 33 patients who died within 30 days of surgery. Of these 32 patients 11 (34 per cent) had residual disease that was not suspected at the time of surgery. The causes of death indicated by the autopsy of these patients were as follows: respiratory, 18; cardiac, 7; pulmonary embolism, 4; hemorrhage, 1; bronchopleural fistula, 1; other, 2. Location of lesions. The anatomic locations of the lung lesions are listed in Fig. 6, along with the median survival of the patients with lesions in those respective locations. The numerical distribution of the lesions seemed to correlate well with size of the lobes of the lung, with 106 lesions in the right upper lobe and only
19 lesions in the middle lobe. While differences are noted in the survival curves of lesions found in all lobes of the lung, the survival was significantly poorer when the primary lesion was found to take origin in the middle lobe. Discussion In this evaluation of the survival of patients with bronchogenic carcinoma who have undergone surgical resection, the major factor which influenced survival was the extent of the tumor at the time of the resection.14, 31 If the tumor was confined to the lung and there was no evidence of direct extension to contiguous structures, or if there was no evidence of
588
The Journal of Thoracic and Cardiovascular Surgery
Vincent et al.
80 e>
i
LEET LEFT RIGHT RIGHT RIGHT
\ \ \\^
UPPER LOWER UPPER MIDDLE LOWER
N= 8 6 N= 4 2 N = I06 N= 19 N= 4 0 N=293
LOBE LOBE LOBE ■ LOBE LOBE TOTAL
60 > or:
40
20 i
20
l
l
40
i
i
60
80
i
100
i
120
TIME IN MONTHS Fig 6. Survival by anatomic site of primary lesions following surgical resection of lung cancer (N = 293, p < 0.05). The median survival in months as related to the site of the primary lesions is as follows: LUL-19.3, LLL-22.7, RUL-14.6, ML-9.6, RLL-25.6. dissemination to adjacent or distant lymph nodes, there was a much greater possibility of an extended survival. Operative deaths became a significant factor in the survival rate when radical pneumonectomy was required to remove the lesion. Considering the lethal characteristics of lung cancer, the operative mortality rate for lobectomy is quite acceptable (1.9 per cent), but an operative mortality rate of 12 per cent for pneumonectomy is the factor that must be weighed judiciously in the preoperative assessment of the lung cancer patient.7,8> I0 ' 1 2 , 2 2 A diagnostic thoracotomy is not an innocuous procedure and has an operative mortality rate that exceeds 4 per cent.27 When thoracotomy is performed as a diagnostic procedure, it is frequently done in a patient in whom advanced disease is suspected and resection is unlikely. Further, the opportunity for postoperative complications is increased considerably by the fact that a major operative procedure has been undertaken with little or no palliative resection of the diseased tissue. The increasing use of mediastinoscopy and mediastinotomy may do much to obviate the need for diagnostic thoracotomy.29 Where intentional reductive or palliative surgery was performed, we experienced a 6.3 per cent 5 year survival rate with a 6 per cent operative mortality rate.
The quality of life in some instances was improved following surgery, but usually this effort has not been exceptionally rewarding to the patient.30 When all cases of lung cancer, regardless of treatment, are considered, squamous-cell carcinoma usually has had the best prognosis, with large-cell carcinoma and adenocarcinoma having a similar but intermediate survival rate and small-cell carcinoma having a characteristically poor survival ratio. 23, 25 However, when the lung lesion has been resected and the surgeon felt that the surgery was a curative procedure, it becomes apparent that, with the exception of small-cell carcinoma, it does not make a great deal of difference in terms of survival which cell type of malignancy was present. 12,14,3U 32 Because of the few 5 year survivals that have been reported following the surgical resection of small-cell carcinoma, it is probably expedient that small-cell carcinoma of the lung should be regarded as a systemic disease, and surgery should be performed only in the most optimal situations.25 One cell type of lung cancer which elicits considerable interest is bronchioalveolar. There has been a tendency in some reports to lump bronchioalveolar carcinoma with adenocarcinoma. In spite of the characteristic multicentricity of bronchioalveolar carcinoma,
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some authors are reporting favorable results with the surgical resection of these lesions.2, 8- 23 In the 18 patients we resected for bronchioalveolar carcinoma we achieved a median survival of 24.4 months. At our Institute we have noted that during the past 10 years there has been a very decided increase in the incidence of adenocarcinoma. While the reasons for this are as yet not evident, we feel that the increasing incidence of lung cancer among women will further contribute to the increasing prevalence of adenocarcinoma among lung cancer patients. Female patients with lung cancer have essentially the same operative mortality and survival rates as do male patients.4, 14 There have been some divergent views concerning the possible distinctive aspects of the cancer of the lung that develops in a patient under 40 years of age. When treating a cancer of the lung in a young patient many clinicians feel that they are dealing with a very aggressive variant of the disease.1' 16, 18, 19' 21 In our opinion, a distinction ought to be made between those patients who are less than 20 years of age and those who are between 20 and 40 years of age at the time they develop carcinoma of the lung.4, 15 Carcinomas of the lung that appear in a patient under 20 years of age may be of an entirely different genesis than those which occur in patients whom have had a longer interval of time to be exposed to environmental carcinogens. Whether this is due to a relative incompetence of the patients' immune systems or whether it is a reflection of a particularly fast-growing lung tumor, or other factors, is yet to be determined. Kellerman and associates have suggested that the presence or absence of the enzyme aryl hydroxylase may well determine the susceptibility of the patient to lung cancer.17 It is reasonable to expect young patients to have a better than average postoperative course and an increased capacity to immunologically defend themselves against the lung tumor. However, a review of the operative mortality and survival data indicates that, while it cannot be clearly stated that young patients with lung cancer do much more poorly than the patients who are older, it can be said that there are no advantages in developing lung cancer at less than 40 years of
Reporting" for lung cancer will do much to facilitate communication of information and data in a manner that can be understood and interpreted with some degree of uniformity. We have applied the principles of "staging" adopted by the American Joint Committee on Staging and End Result Reporting. We detect a statistically significant difference in survival between Stage I and Stages II and HI but at present do not observe a significant difference in survival between Stage II and Stage III in the resected patient. Some authors have reported that they have achieved a significant 5 year survival when hilar nodes were involved and even more remarkably when mediastinal nodes were positive.32, 34 We are unable to achieve these results, noting that whenever the disease has the capacity to metastasize anywhere, it shortly thereafter develops the ability to concomitantly metastasize everywhere. This would lead us to question the logic of the proposal by the American Committee on Staging and End Result Reporting to categorize a T,N,M„ lesion as a Stage I lesion. Matthews and associates24 have reported previously, and we verify with our autopsy data, that in 35 per cent of the preoperative assessment of lung cancer patients the presence of disseminated disease is unappreciated. In this series 34 per cent of the patients that came to autopsy within 30 days of surgery had disseminated disease that was not clinically apparent prior to surgery.3 In our preoperative assessment we missed lesions later found at autopsy of the adrenal, kidney, bone, mediastinum, and liver. The diagnostic techniques currently available to us are adequate to permit us to operate with confidence that a curative resection is technically possible in only two out of every three patients. Spjut and associates34 reported that primary cancer of the right lung had a more favorable prognosis than cancer in the left lung. We found a significant decrease in the survival rate among patients with primary lung cancer of the middle lobe but no significant difference between other lobes or in the right lung as compared to the left lung.
ogg 20, 26, 28
Summary
Since at this time cure can be expected only with surgical resection, one is inclined to operate on the elderly or those over 70 years of age whenever this seems reasonable. The morbidity, mortality, and survival rates are acceptable in patients operated on in this age range if there is a very careful assessment and selection of the patient.35, 36 A standard method of "Staging and End Result
Clinical data derived from 295 patients who underwent surgical resection for carcinoma of the lung have provided us with an assessment of a number of factors that may be significant in prolonging survival. The major factor influencing survival was primarily the extent of the tumor at the time of resection. When metastatic lymph nodes were found at the time of surgery, regardless of the location, the survival rate
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was significantly less than in patients who demonstrated no evidence of metastases. With the exception of small-cell carcinoma we found that the histology of the tumors seems to make little difference in survival when the surgeon felt that a curative resection had been accomplished. We have observed a marked increase in the incidence of adenocarcinoma during the past 10 years. We have also noted a twofold increase in the incidence of cancer of the lung in women and that these lesions are predominatly adenocarcinoma. The operative mortality and survival rates are about the same in men and women. The age of diagnosis is not a major factor in terms of operative mortality or survival rates, but there is no advantage to the patient in developing cancer of the lung before the age of 40. We found that the principles established by the "American Joint Committee on Staging and End Result Reporting" for lung cancer were valid and very helpful in staging the lesions reported in this series. Autopsy data available on these patients would indicate that our preoperative assessment of the patient is incorrect in 34 per cent of the patients as to the presence or absence of disseminated disease. The location of the primary lung lesion in the middle lobe was particularly ominous but there seems to be no predilection for lung cancer in any specific lobe or lung and, with the exception of the middle lobe the location of the lesion did not significantly influence the length of survival. We gratefully acknowledge the assistance of Ms. Tona Flak in the preparation of the manuscript, Ms. Gail Beaver in patient staging procedures and data processing, James Didinsky, Alexander Khandji, and Maximo C. Garcia, Jr., M.D., for review and editing of manuscript. REFERENCES 1 Anderson A. E., Buechner, H. A., Yager, I., and Ziskind, M. D.: Bronchogenic Carcinoma in Young Men, Am. J. Med. 16: 404, 1954. 2 Barrett, R. J., Day, J. C , O'Rourke, P. V., Chapman, P. T., Sadeghi, H., Perry, R. W., and Tuttle, W. M.: Primary Carcinoma of the Lung. Experience with 1,312 Patients. J. THORAC. CARDIOVASC. SURG. 46: 292, 1963.
3 Beil, R., and Tortolani, A. J.: Survival of Lung Cancer Patients in a Community Hospital, Proc. Natl. Conf. 7: 747, 1973. 4 Belcher, J. R., and Anderson R.: Surgical Treatment of Carcinoma of the Bronchus, Br. Med. J. 1: 948, 1965. 5 Bignall, J. R., Martin, M., and Smithers, D. W.: Survival in 6,086 Cases of Bronchial Carcinoma, Lancet 1: 1067, 1967.
The Journal of Thoracic and Cardiovascular Surgery
6 Breslow, N.: A Generalized Kruskal-Wallis Test for Comparing K Samples Subject to Unequal Patterns of Censorship, Biometrika 57: 579, 1970. 7 Boucot, K., Cooper, D. A., and Weiss, W.: The Role of Surgery in the Cure of Lung Cancer, Arch. Intern. Med. 120: 168, 1967. 8 Burford, T. H., Center, S., Ferguson, T. B., and Spjut, H. J.: Results in the Treatment of Bronchogenic Carcinoma, J. THORAC. SURG. 36: 316, 1958.
9 Cutler, S. J., and Ederer, F.: Maximum Utilization of the Life Table Method in Analyzing Data, J. Chron. Dis. 8: 699, 1958. 10 Dillon, M. L., and Postlethwait, R. W.: Carcinoma of the Lung, Ann. Thorac. Surg. 11: 193, 1971. 11 Eastridge, C. E., Hughes, F. A., Jr., and Greenberg, B. E.: Primary Carcinoma of the Lung. Treatment of 1,284 Cases, Am. Surg. 33: 700, 1967. 12 Galofre, M., Payne, W. S., Woolner, L. B., Clagett, O. T., and Gage, R. P.: Pathologic Classification and Surgical Treatment of Bronchogenic Carcinoma, Surg. Gynecol. Obstet. 119: 51, 1964. 13 Graham, E. A., and Singer, J. J.: Successful Removal of Entire Lung for Carcinoma of the Bronchus, J. A. M. A. 101: 1371, 1933. 14 Green, N., Kurohara, S. S., and George, F. W. Ill: Cancer of the Lung, Cancer 28: 1229, 1971. 15 Hanbury, W. J.: Bronchogenic Carcinoma in Young Persons, Br. J. Cancer 12: 202, 1958. 16 Hood, R. H. Jr., Campbell, D. C. Jr., Dooley, B. N., and Dooling, J. A.: Bronchogenic Carcinoma in Young People, Chest 48: 469, 1965. 17 Kellerman, G., Shaw, C. R., and Luyten-Kellerman, M.: Aryl Hydrocarbon Hydroxylase Inducibility in Bronchogenic Carcinoma, N. Engl. J. Med. 289: 934, 1973. 18 Kennedy, A.: Lung Cancer in Young Adults, Br. J. Dis. Chest 66: 147, 1972. 19 Kwong, K. H., and Slade, P. R.: Carcinoma of the Bronchus in Young Adults, Br. J. Tuberc. 52: 185, 1958. 20 Kyriakos, M., and Webber, B.: Cancer of the Lung in Young Men, J. THORAC. CARDIOVASC. SURG. 67: 634,
1974. 21 Large, S. E., and Morgan, W. K. C : Bronchial Carcinoma in Young Adults, Br. J. Tuberc. 52: 185, 1958. 22 Lee, Y.: Thoracotomy for Lung Cancer. Review of Experiences at a Cancer Hospital, Am. Surg. 39: 410, 1973. 23 Martini, N., Cliffton, E. E., and Beattie, E. J.: Survival of Lung Cancer Patients Vis-a-Vis Therapy and Cell Type, Proc. Natl. Conf. 7: 739, 1973. 24 Matthews, M., Kanhouwa, S., Pickren, J., and Robinette, D.: Frequency of Residual and Metastatic Tumor in Patients Undergoing Curative Resection for Lung Cancer, Cancer Chemother. Rep. 4: 63, 1973. 25 Mountain, C. F.: Surgical Therapy in Lung Cancer: Biologic, Physiologic and Technical Determinants, Sem. Oncol. 1: 3, 1974.
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Surgical therapy of lung cancer
26 Neuman, H. W., Ellis, F. H., and McDonald, J. R.: Bronchogenic Carcninoma in Persons Under Forty Years of Age, N. Engl. J. Med. 254: 502, 1956. 27 Paulson, D. L.: Selection of Patients for Surgery for Bronchogenic Carcinoma, Am. Surg. 39: 1, 1973. 28 Rivkin, L. M., and Salyer, J. M.: Bronchogenic Carcinoma in Men Under 40 Years of Age, Dis. Chest 34: 521, 1958. 29 Sealy, W. C : Mediastinoscopy: Does It Have a Place in the Management of Carcinoma of the Lung. Ann. Thorac. Surg. 18: 433, 1974. 30 Shields, T. W.: The Fate of Patients After Incomplete Resection of Bronchial Carcinoma, Surg. Gynecol. Obstet. 139: 569, 1974. 31 Shields T. W., Higgins, G. A., and Keehn, R. J.: Factors Influencing Survival After Resection for Bronchial Carcinoma, J. THORAC. CARDIOVASC. SURG. 64:
1972.
391,
591
32 Shields, T. W., Yee, J., Conn, J. H. and Robinette, C. D.: Relationship of Cell Type and Lymph Node Metastasis to Survival After Resection of Bronchial Carcinoma, Ann. Thorac. Surg. 20: 5, 1975. 33 Slack, N. H., Chamberlain, A., and Bross, I. D. J.: Predicting Survival Following Surgery for Bronchogenic Carcinoma, Chest: 62: 433, 1972. 34 Spjut, H. J., Roper, C. L., and Butcher, H. R.: Pulmonary Cancer and Its Prognosis, Cancer 14: 1251, 1961. 35 Weiss, W.: Operative Mortality and Five-Year Survival Rates in Men with Bronchogenic Carcinoma, Chest 66: 483, 1974. 36 Weiss, W.: Operative Mortality and Five-Year Survival Rates in Patients with Bronchogenic Carcinoma, Am. J. Surg. 128: 799 , 1974.
J. he first successful pneumonectomy for cancer of the lung was performed by Graham and Singer13 in 1933. Since 1933 both the incidence of and the deaths from lung cancer have increased more than 20-fold in men, and have increased steadily among women, but to a lesser degree. Surgery has been established as the form of therapy in which cure might best be anticipated under circumstances where a preoperative assessment has accurately established the presence of limited primary disease.5' 8' n ' 12, 22, 33 The therapeutic limitations of surgery are also now well recognized, and future progress in preventing or controlling this disease is contingent upon finding methods which will either supplant or enhance the therapeutic effectiveness of surgery. 2,4 - 7 The purpose of this study is to assess the factors of histology, sex, stage, age, tumor location, and types of surgical procedures as they relate to the possible curative resection of lung cancer. Materials and methods At Roswell Park Memorial Institute, between the years of 1963 and 1974, 1,615 patients were treated with a histologically established diagnosis of primary lung cancer. Roswell Park Memorial Institute is maintained solely for the benefit of cancer patients. For this reason, the From the Roswell Park Memorial Institute, Buffalo N. Y. Supported in part by NCI Contract N01-CM-33734. Received for publication Aug. 6, 1975. Address for reprints: Ronald G. Vincent, M.D., Chief of Thoracic Surgery, Roswell Park Memorial Institute, Buffalo, N. Y.
patient population may be somewhat different from that of a community hospital.3 A total of 567 (35.1 per cent) of these patients were surgically explored; 295 (18.3 per cent) received surgical resection of their lung lesion and 272 (16.8 per cent) had a diagnostic thoracotomy with biopsy but without resection. All surgically excised lung specimens were examined further to ascertain the presence of lymph nodes, and the number and location of nodes involved by cancer were recorded. Histological confirmation of suspected mediastinal nodes was obtained and recorded along with the documentation of direct tumor invasion of the mediastinum or chest wall. All patients were "clinically" staged according to the methods established by the American Joint Committee on Staging and End Results Reporting and all surgical patients were staged again following surgery by the same methods (Table I). Eleven patients were lost to follow-up and for statistical purposes are presumed to be dead. The autopsy rate at Roswell Park Memorial Institute is 95 per cent of all patients who die on the premises. Deaths that occurred within 30 days of surgery are considered operative deaths and these patients are included in all of the statistical assessments that follow. Survival is based on the Cutler and Ederer9 life table method. A wedge or segmental resection was usually performed under those circumstances where the patient's pulmonary reserve was compromised to the degree that resection of large amounts of lung tissue was not deemed wise. A radical pneumonectomy is defined as a surgical procedure which requires removal 5 81
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Table I. Work sheet for staging lung cancer No.: Name: Directions: Encircle the T, N, and M rating following the description that is most accurate for the patient's cancer. Encircle the value for each rating and add to obtain the total value. Consult the table at the bottom of the form to determine the stage . . . If patient had a thoracotomy, the surgical evaluative (postthoracotomy) classification may be entered on this same form. Similarly, if patient had a resection, the postsurgical treatment classification may be entered on this form. Classification Surgical evaluative value
Clinical value Primary tumor—T No evidence of primary tumor Tumor proved by the presence of malignant cells in secretions but not visualized roentgenographically or bronchoscopically A tumor that is 3.0 cm. or less in greatest diameter, surrounded by lung or visceral pleura and without evidence of invasion proximal to a lobar bronchus at bronchoscopy A tumor more than 3.0 cm. in greatest diameter or a tumor of any size which, with its associated atelectasis or obstructive pneumonitis, extends to the hilar region. At bronchoscopy the proximal extent of demonstrable tumor must be at least 2.0 cm. distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung and there must be no pleural effusion A tumor of any size with direct extension into an adjacent structure such as the chest wall, the diaphragm, or the mediastinum and its contents; or demonstrable bronchoscopically to be less than 2.0 cm. distal to the carina; or any tumor associated with atelectasis or obstructive pneumonitis of an entire lung or a pleural effusion Regional lymph nodes—N: No demonstrable spread to regional lymph nodes Spread to lymph nodes in the ipsilateral hilar region Spread to lymph nodes in the mediastinum Distant metastasis—M: No distant metastasis Distant metastasis such as in scalene, cervical, or contralateral hilar lymph nodes, brain, lung, liver, etc. Total value 0 1 or 2 3 4 or more
Stage Occult carcinoma I II III
TO TX
0 0
TO TX
Postsurg. treatment value 0 0
TO TX
Tl
Tl
Tl
T2
T2
T2
T3
T3
4
T3
0 0
NO Nl N2
0 1 4
NO Nl N2
0 1 4
NO Nl N2
0 1 4
MO Ml
0 4
MO Ml
0 4
MO Ml
0 4
T N M Stage
Summary of staging T T N N M M Stage Stage
Cell type: squamous, □; small, □; adenocarcinoma, □; large, Q; unknown, □. If patient had a resection, indicate whether postsurgical treatment classification was based on pathological evaluation of: Primary tumor mass □ yes D no □ unknown Regional lymph nodes □ yes D no □ unknown Distant sites □ yes D no □ unknown
of direct tumor extension to the mediastinum, pericardium, diaphragm, or chest wall. Results Type of surgery. The median survival time of the 295 patients who underwent a definitive surgical
resection was 17.5 months, with a 5 year survival of 17.3 per cent. Included in these 295 patients were 67 patients in whom an incomplete resection or intentional palliative resection was performed. In these 67 cases invasion of the chest wall, mediastinum, or bronchus caused the surgeon to doubt that there had been a total
Volume 71 Number 4 April, 1976
Surgical therapy of lung cancer
lOOr
WEDGE/SEQ. LOBECTOMY PNEUMONECTOMY RAD. PNEUMONECTOMY
V
80
M
5 83
N=I60 N=IOI N = 30
\
? 60 > > oc w 40
\
\
\
1
20
^
"V.
x
\
—•*-.
" '
*'—T
1,
20
40
\-.
i
60
.
.
.
.i
80
100
i
120
TIME IN MONTHS Fig. 1. Survival by type of surgical resection for lung cancer (N = 295). Table II. Postoperative mortality and survival rates for lung cancer* Surgical therapy Wedge or Segmental Lobectomy Pneumonectomy Radical pneumonectomy Total resections Thoracotomy without resection Palliative or reductive
No.
Per cent of total
30 day mortality rate
<%)
Median survival (mo.)
5 yr. survival
10 yr. survival
<%)
(%)
>47t
==66.7t
< 66.7t
4
1.4
0
160 101 30
54.2 34.2 10.2
1.9 11.9 20.0
24.1 11.2 5.9
20.1 15.3 0
20.1 8.0 0
295
100
7.1
17.5
17.3
13.3
272
100
4.1
6.0
0.6
s0.6t
67
100
6.0
11.6
6.3
<6.3t
*Chi square = 21.5; DF = 3; P < 0.001 (omitting wedge/segmental). tTime not reached.
ablation of the tumor by the surgical resection of the lung. Usually the presence of residual disease was verified by histological examination. Since the possibility of viable residual disease was evident to the surgeon, additional therapy, such as radiotherapy, was frequently instituted. These 67 patients had an operative mortality rate of 6.0 per cent, a median survival rate of 11.6 months, and a 6.3 per cent 5 year survival (Table II).
The survival data also show an operative mortality rate of 1.9 per cent for lobectomies, 11.9 per cent for pneumonectomies, and 20 per cent for radical pneumonectomies, with an over-all operative mortality rate of 7.1 per cent for all resected cases. The operative mortality rate, the median survival rate and the per cent of 5 and 10 year survival0 ~.s they relate to the types of surgery performed are all given in Table II. As the magnitude of surgery required for the resection of the
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N=I6I N = I6 N=I7 N = 72 N = I8 N=M
40
60
80
100
120
TIME IN MONTHS Fig. 2. Survival by histologic cell type following surgical resection of lung cancer (N = 295). Table III. Postoperative mortality and survival rates for lung cancer: Surgical resections by histology*
Cell type
No.
Per cent of total
Squamous Adeno Large Small Bronchoalveolar Undifferentiated Total
161 72 17 16 18 11 295
54.6 24.4 5.8 5.4 6.1 3.7 100
30 day mortality rate {%)
Median survival (mo.)
Syr. survival
(%)
<%)
5.0 8.4 5.9 25.0 11.1 9.1 7.1
19.3 23.2 10.0 5.5 24.4 18.5 17.5
19.9 11.4 20.9 0 18.2 18.2 17.3
15.3 0 20.9 0 18.2 S18.2t 13.3
10 yr. survival
*Chi square = 12.1; DF ■■5; P < 0.05. tTime not reached.
tumor increased, the operative mortality rate increased, and the median and 5 year survival rates decreased (Fig. 1). The value of intentional reductive surgery or palliative surgery must be considered in view of experience where thoracotomy is performed but a resection is not achieved. There were 272 patients at this Institution between 1963 and 1974 who had a diagnostic thoracotomy but without resection. The operative mortality rate was 4.1 per cent, with a median survival of 6.0 months and a 5 year survival of 0.6 per cent (Table II). Histology. During the period between 1963 and
1974 the histological findings of the tumors of 1,615 patients treated for lung cancer were distributed by cell type as follows: squamous cell, 39.6 per cent; adenocarcinoma, 23.2 per cent; small cell, 18.4 per cent, large cell, 8.6 per cent; bronchioalveolar, 2.8 per cent; and undifferentiated, 7.4 per cent. Of all the lung tumors that were resected, 161 were squamous-cell carcinoma and only 16 (5.4 per cent) were small-cell carcinoma, suggesting that a squamous-cell carcinoma is the cell type most amenable to surgical resection and that small-cell carcinoma is rarely resected successfully. The operative mortality rate as well as the median and 5 year survival rates for
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Surgical therapy of lung cancer
585
lOOr MALE FEMALE
40
60
N = 247 N = 48
80
120
TIME IN MONTHS Fig. 3. Survival by sex following surgical resection of lung cancer (N = 295, p > 0.05). Male median survival 16.1 months; female median survival 23.1 months. these two cell types would also tend to substantiate this observation (Table III). In the 295 patients who had a pulmonary resection of their lung cancer, no significant difference can be noted in the survival of the resected patient with regard to tumor histology, although small-cell carcinoma has a uniformly poor prognosis (Fig.2). Sex. During the period of this study, the incidence of lung cancer among females has doubled. In 1963 at Roswell Park Memorial Institute the ratio of men to women treated for lung cancer was 9 : 1 . Each year subsequently the incidence of lung cancer among women increased until 1974, when the ratio of men to women became 4 : 1 . Women also had a greater incidence of adenocarcinoma (34 per cent) and small-cell carcinoma (26 per cent) than did men. These facts, however, did not significantly influence the operative mortality rate or the over-all survival rate which is essentially the same as it is with men (Fig. 3). Age at diagnosis. The decision to perform major surgery on a patient who is deemed resectable but is over 70 years of age is usually made with great restraint. There may also be a tendency to be more aggressive in performing surgery in younger patients. We found the operative mortality and median survival rates to be essentially the same in all patients between 40 and 70 years of age who were selected for resection.
Table IV. Postoperative mortality and survival rates for lung cancer: Surgical resections by age*
Age (yr.)
No.
20-40 8 40-49 46 50-59 95 60-69 106 70+ 40 Total 295
Per cent of total 2.7 15.6 32.2 35.9 13.6 100
30 day 5 yr. mortality Median survival survival rate <%) (mo.) (%) 12.5 4.4 7.4 8.5 7.5 7.1
14.1 18.6 16.8 19.4 14.2 17.5
0 20.3 21.5 15.9 7.8 17.3
10 yr. survival
<%) 0 20.3 14.4 11.3 <7.8t 13.3
*Chi square = 3.9 DF = 4; P > 0.05. fTime not reached.
However, the percentage of 5 year and 10 year survival is reduced among patients who were treated and were over 70 or under 40 years of age at the time of diagnosis (Table IV). The median age at the time of surgery was 60.7 for men and 53.3 for women. Stage of disease. All patients in this study were "clinically" and "surgically" staged according to the methods adopted by the American Joint Committee on Staging and End Results Reporting (Table I). Those patients who demonstrated no evidence of metastasis or dissemination (Stage I) had a significantly better survival than those patients with either ipsilateral
5 86
The Journal of Thoracic and Cardiovascular Surgery
Vincent et al.
80
o z
> > rr
O (O
STAGE I STAGE H STAGE M
lA
A
N=I38 N= 58 N= 99
60
40 -
\
\ \
20
"v.
\
i
v., *\. \
--^v
i
1
1
1
20
40
60
80
1
100
1
120
TIME IN MONTHS Fig. 4. Survival by stage following surgical resection of lung cancer (N = 295).
Table V. Postoperative mortality and survival rates for lung cancer: Surgical resections by stage*
Stage No. I II III Total
138 58 99 295
Per cent of total 46.8 19.7 33.5 100
30 day mortality rate
<%) 5.1 6.9 10.2 7.1
Median survival (mo.)
5 yr. survival
10 yr. survival
<%)
(%)
26.7 14.7 8.0 17.5
28.8 6.9 6.9 17.3
23.3 S3.5t s6.9t 13.3
*Chi square = 31.3; DF = 2 P < 0.001. tTime not rea:hed.
hilar node metastasis (Stage II) or those with distant metastasis and/or direct extension into adjacent structures (Stage III) (Fig. 4). P < 0.001.* The operative mortality rate was increased and the median survival rate decreased in resected Stage III disease (Table V). Lymph node involvement. With each surgical resection, suspicious nodes in the mediastinum were biopsied and, where feasible, were removed with the surgical specimen. Each lung removed at surgery was examined for the presence of nodes and, where found, *The Breslow Test is used for all assessments of statistical significance.6
their location and pathology, if any, were noted. Of the 295 patients that underwent surgical resection, 183 (62 per cent) were felt not to have had metastasis to lymph nodes at the time of surgery. The median survival of this group was 21.2 months, with a 5 year survival of 24.8 per cent (Table VI). The ages of patients found with positive lymph nodes at the time of surgery are listed by cell type as follows: squamous, 35 per cent; adenocarcinoma, 44 per cent; large-cell carcinoma, 47 per cent; small-cell carcinoma, 38 per cent. Where metastatic nodes were found at surgery, median survival became less than 14.1 months. A 5 year survival of 24.8 per cent was achieved when no metastatic nodes were evident at the time of surgery but if nodes were evident there were no 5 year survivors. We were unable to detect any prognostic distinction between the metastatic involvement of hilar nodes and the metastatic involvement of mediastinal nodes. (Fig. 5). This would suggest to us that once a tumor has demonstrated a propensity for dissemination, it rarely limits this capacity to the immediate vicinity of the primary tumor. Autopsies. Autopsies were performed on 34.6 per cent of the 295 patients who had surgical resection of their lung lesion. Eighteen (17.6 per cent) of these patients had no evidence of residual tumor at the time of death.
Volume 71 Number 4 April, 1976
Surgical therapy of lung cancer
80 o z > >
rr 3
l \ 'jl
^
60 -
NONE HILAR MEDIASTINAL
S?
* \
V
\
- vV vs\ \
1
20
N=I83 N = 60 N = 52
v\ \
40
587
"1
x.-.. \ -v\ W-I
i
i
20
40
*—-
w—. \_.L
V
i
I
60
80
\
I
.
i
100
120
TIME IN MONTHS Fig. 5. Survival by metastatic node involvement following surgical resection of lung cancer (N
295).
Table VI. Postoperative mortality and survival rates for lung cancer: Surgical resections by node metastasis*
Metastatic lymph nodes No nodes Hilar nodes only Mediastinal nodes Total
30 day mortality rate
5 yr. survival
10 yr. survival
(%)
Median survival (mo.)
(%)
(%)
No.
Per cent of total
183 60
62.0 20.4
6.6 5.0
21.2 13.3
24.8 0
20.5 0
52
17.6
11.5
14.1
4.3
0
295
loo"
~1~A
Tr?
~H3
13.3
•Chi square = 7.3; DF = 2; P < 0.05.
Of particular interest were the autopsies performed on 32 of the 33 patients who died within 30 days of surgery. Of these 32 patients 11 (34 per cent) had residual disease that was not suspected at the time of surgery. The causes of death indicated by the autopsy of these patients were as follows: respiratory, 18; cardiac, 7; pulmonary embolism, 4; hemorrhage, 1; bronchopleural fistula, 1; other, 2. Location of lesions. The anatomic locations of the lung lesions are listed in Fig. 6, along with the median survival of the patients with lesions in those respective locations. The numerical distribution of the lesions seemed to correlate well with size of the lobes of the lung, with 106 lesions in the right upper lobe and only
19 lesions in the middle lobe. While differences are noted in the survival curves of lesions found in all lobes of the lung, the survival was significantly poorer when the primary lesion was found to take origin in the middle lobe. Discussion In this evaluation of the survival of patients with bronchogenic carcinoma who have undergone surgical resection, the major factor which influenced survival was the extent of the tumor at the time of the resection.14, 31 If the tumor was confined to the lung and there was no evidence of direct extension to contiguous structures, or if there was no evidence of
588
The Journal of Thoracic and Cardiovascular Surgery
Vincent et al.
80 e>
i
LEET LEFT RIGHT RIGHT RIGHT
\ \ \\^
UPPER LOWER UPPER MIDDLE LOWER
N= 8 6 N= 4 2 N = I06 N= 19 N= 4 0 N=293
LOBE LOBE LOBE ■ LOBE LOBE TOTAL
60 > or:
40
20 i
20
l
l
40
i
i
60
80
i
100
i
120
TIME IN MONTHS Fig 6. Survival by anatomic site of primary lesions following surgical resection of lung cancer (N = 293, p < 0.05). The median survival in months as related to the site of the primary lesions is as follows: LUL-19.3, LLL-22.7, RUL-14.6, ML-9.6, RLL-25.6. dissemination to adjacent or distant lymph nodes, there was a much greater possibility of an extended survival. Operative deaths became a significant factor in the survival rate when radical pneumonectomy was required to remove the lesion. Considering the lethal characteristics of lung cancer, the operative mortality rate for lobectomy is quite acceptable (1.9 per cent), but an operative mortality rate of 12 per cent for pneumonectomy is the factor that must be weighed judiciously in the preoperative assessment of the lung cancer patient.7,8> I0 ' 1 2 , 2 2 A diagnostic thoracotomy is not an innocuous procedure and has an operative mortality rate that exceeds 4 per cent.27 When thoracotomy is performed as a diagnostic procedure, it is frequently done in a patient in whom advanced disease is suspected and resection is unlikely. Further, the opportunity for postoperative complications is increased considerably by the fact that a major operative procedure has been undertaken with little or no palliative resection of the diseased tissue. The increasing use of mediastinoscopy and mediastinotomy may do much to obviate the need for diagnostic thoracotomy.29 Where intentional reductive or palliative surgery was performed, we experienced a 6.3 per cent 5 year survival rate with a 6 per cent operative mortality rate.
The quality of life in some instances was improved following surgery, but usually this effort has not been exceptionally rewarding to the patient.30 When all cases of lung cancer, regardless of treatment, are considered, squamous-cell carcinoma usually has had the best prognosis, with large-cell carcinoma and adenocarcinoma having a similar but intermediate survival rate and small-cell carcinoma having a characteristically poor survival ratio. 23, 25 However, when the lung lesion has been resected and the surgeon felt that the surgery was a curative procedure, it becomes apparent that, with the exception of small-cell carcinoma, it does not make a great deal of difference in terms of survival which cell type of malignancy was present. 12,14,3U 32 Because of the few 5 year survivals that have been reported following the surgical resection of small-cell carcinoma, it is probably expedient that small-cell carcinoma of the lung should be regarded as a systemic disease, and surgery should be performed only in the most optimal situations.25 One cell type of lung cancer which elicits considerable interest is bronchioalveolar. There has been a tendency in some reports to lump bronchioalveolar carcinoma with adenocarcinoma. In spite of the characteristic multicentricity of bronchioalveolar carcinoma,
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Surgical therapy of lung cancer
589
some authors are reporting favorable results with the surgical resection of these lesions.2, 8- 23 In the 18 patients we resected for bronchioalveolar carcinoma we achieved a median survival of 24.4 months. At our Institute we have noted that during the past 10 years there has been a very decided increase in the incidence of adenocarcinoma. While the reasons for this are as yet not evident, we feel that the increasing incidence of lung cancer among women will further contribute to the increasing prevalence of adenocarcinoma among lung cancer patients. Female patients with lung cancer have essentially the same operative mortality and survival rates as do male patients.4, 14 There have been some divergent views concerning the possible distinctive aspects of the cancer of the lung that develops in a patient under 40 years of age. When treating a cancer of the lung in a young patient many clinicians feel that they are dealing with a very aggressive variant of the disease.1' 16, 18, 19' 21 In our opinion, a distinction ought to be made between those patients who are less than 20 years of age and those who are between 20 and 40 years of age at the time they develop carcinoma of the lung.4, 15 Carcinomas of the lung that appear in a patient under 20 years of age may be of an entirely different genesis than those which occur in patients whom have had a longer interval of time to be exposed to environmental carcinogens. Whether this is due to a relative incompetence of the patients' immune systems or whether it is a reflection of a particularly fast-growing lung tumor, or other factors, is yet to be determined. Kellerman and associates have suggested that the presence or absence of the enzyme aryl hydroxylase may well determine the susceptibility of the patient to lung cancer.17 It is reasonable to expect young patients to have a better than average postoperative course and an increased capacity to immunologically defend themselves against the lung tumor. However, a review of the operative mortality and survival data indicates that, while it cannot be clearly stated that young patients with lung cancer do much more poorly than the patients who are older, it can be said that there are no advantages in developing lung cancer at less than 40 years of
Reporting" for lung cancer will do much to facilitate communication of information and data in a manner that can be understood and interpreted with some degree of uniformity. We have applied the principles of "staging" adopted by the American Joint Committee on Staging and End Result Reporting. We detect a statistically significant difference in survival between Stage I and Stages II and HI but at present do not observe a significant difference in survival between Stage II and Stage III in the resected patient. Some authors have reported that they have achieved a significant 5 year survival when hilar nodes were involved and even more remarkably when mediastinal nodes were positive.32, 34 We are unable to achieve these results, noting that whenever the disease has the capacity to metastasize anywhere, it shortly thereafter develops the ability to concomitantly metastasize everywhere. This would lead us to question the logic of the proposal by the American Committee on Staging and End Result Reporting to categorize a T,N,M„ lesion as a Stage I lesion. Matthews and associates24 have reported previously, and we verify with our autopsy data, that in 35 per cent of the preoperative assessment of lung cancer patients the presence of disseminated disease is unappreciated. In this series 34 per cent of the patients that came to autopsy within 30 days of surgery had disseminated disease that was not clinically apparent prior to surgery.3 In our preoperative assessment we missed lesions later found at autopsy of the adrenal, kidney, bone, mediastinum, and liver. The diagnostic techniques currently available to us are adequate to permit us to operate with confidence that a curative resection is technically possible in only two out of every three patients. Spjut and associates34 reported that primary cancer of the right lung had a more favorable prognosis than cancer in the left lung. We found a significant decrease in the survival rate among patients with primary lung cancer of the middle lobe but no significant difference between other lobes or in the right lung as compared to the left lung.
ogg 20, 26, 28
Summary
Since at this time cure can be expected only with surgical resection, one is inclined to operate on the elderly or those over 70 years of age whenever this seems reasonable. The morbidity, mortality, and survival rates are acceptable in patients operated on in this age range if there is a very careful assessment and selection of the patient.35, 36 A standard method of "Staging and End Result
Clinical data derived from 295 patients who underwent surgical resection for carcinoma of the lung have provided us with an assessment of a number of factors that may be significant in prolonging survival. The major factor influencing survival was primarily the extent of the tumor at the time of resection. When metastatic lymph nodes were found at the time of surgery, regardless of the location, the survival rate
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was significantly less than in patients who demonstrated no evidence of metastases. With the exception of small-cell carcinoma we found that the histology of the tumors seems to make little difference in survival when the surgeon felt that a curative resection had been accomplished. We have observed a marked increase in the incidence of adenocarcinoma during the past 10 years. We have also noted a twofold increase in the incidence of cancer of the lung in women and that these lesions are predominatly adenocarcinoma. The operative mortality and survival rates are about the same in men and women. The age of diagnosis is not a major factor in terms of operative mortality or survival rates, but there is no advantage to the patient in developing cancer of the lung before the age of 40. We found that the principles established by the "American Joint Committee on Staging and End Result Reporting" for lung cancer were valid and very helpful in staging the lesions reported in this series. Autopsy data available on these patients would indicate that our preoperative assessment of the patient is incorrect in 34 per cent of the patients as to the presence or absence of disseminated disease. The location of the primary lung lesion in the middle lobe was particularly ominous but there seems to be no predilection for lung cancer in any specific lobe or lung and, with the exception of the middle lobe the location of the lesion did not significantly influence the length of survival. We gratefully acknowledge the assistance of Ms. Tona Flak in the preparation of the manuscript, Ms. Gail Beaver in patient staging procedures and data processing, James Didinsky, Alexander Khandji, and Maximo C. Garcia, Jr., M.D., for review and editing of manuscript. REFERENCES 1 Anderson A. E., Buechner, H. A., Yager, I., and Ziskind, M. D.: Bronchogenic Carcinoma in Young Men, Am. J. Med. 16: 404, 1954. 2 Barrett, R. J., Day, J. C , O'Rourke, P. V., Chapman, P. T., Sadeghi, H., Perry, R. W., and Tuttle, W. M.: Primary Carcinoma of the Lung. Experience with 1,312 Patients. J. THORAC. CARDIOVASC. SURG. 46: 292, 1963.
3 Beil, R., and Tortolani, A. J.: Survival of Lung Cancer Patients in a Community Hospital, Proc. Natl. Conf. 7: 747, 1973. 4 Belcher, J. R., and Anderson R.: Surgical Treatment of Carcinoma of the Bronchus, Br. Med. J. 1: 948, 1965. 5 Bignall, J. R., Martin, M., and Smithers, D. W.: Survival in 6,086 Cases of Bronchial Carcinoma, Lancet 1: 1067, 1967.
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6 Breslow, N.: A Generalized Kruskal-Wallis Test for Comparing K Samples Subject to Unequal Patterns of Censorship, Biometrika 57: 579, 1970. 7 Boucot, K., Cooper, D. A., and Weiss, W.: The Role of Surgery in the Cure of Lung Cancer, Arch. Intern. Med. 120: 168, 1967. 8 Burford, T. H., Center, S., Ferguson, T. B., and Spjut, H. J.: Results in the Treatment of Bronchogenic Carcinoma, J. THORAC. SURG. 36: 316, 1958.
9 Cutler, S. J., and Ederer, F.: Maximum Utilization of the Life Table Method in Analyzing Data, J. Chron. Dis. 8: 699, 1958. 10 Dillon, M. L., and Postlethwait, R. W.: Carcinoma of the Lung, Ann. Thorac. Surg. 11: 193, 1971. 11 Eastridge, C. E., Hughes, F. A., Jr., and Greenberg, B. E.: Primary Carcinoma of the Lung. Treatment of 1,284 Cases, Am. Surg. 33: 700, 1967. 12 Galofre, M., Payne, W. S., Woolner, L. B., Clagett, O. T., and Gage, R. P.: Pathologic Classification and Surgical Treatment of Bronchogenic Carcinoma, Surg. Gynecol. Obstet. 119: 51, 1964. 13 Graham, E. A., and Singer, J. J.: Successful Removal of Entire Lung for Carcinoma of the Bronchus, J. A. M. A. 101: 1371, 1933. 14 Green, N., Kurohara, S. S., and George, F. W. Ill: Cancer of the Lung, Cancer 28: 1229, 1971. 15 Hanbury, W. J.: Bronchogenic Carcinoma in Young Persons, Br. J. Cancer 12: 202, 1958. 16 Hood, R. H. Jr., Campbell, D. C. Jr., Dooley, B. N., and Dooling, J. A.: Bronchogenic Carcinoma in Young People, Chest 48: 469, 1965. 17 Kellerman, G., Shaw, C. R., and Luyten-Kellerman, M.: Aryl Hydrocarbon Hydroxylase Inducibility in Bronchogenic Carcinoma, N. Engl. J. Med. 289: 934, 1973. 18 Kennedy, A.: Lung Cancer in Young Adults, Br. J. Dis. Chest 66: 147, 1972. 19 Kwong, K. H., and Slade, P. R.: Carcinoma of the Bronchus in Young Adults, Br. J. Tuberc. 52: 185, 1958. 20 Kyriakos, M., and Webber, B.: Cancer of the Lung in Young Men, J. THORAC. CARDIOVASC. SURG. 67: 634,
1974. 21 Large, S. E., and Morgan, W. K. C : Bronchial Carcinoma in Young Adults, Br. J. Tuberc. 52: 185, 1958. 22 Lee, Y.: Thoracotomy for Lung Cancer. Review of Experiences at a Cancer Hospital, Am. Surg. 39: 410, 1973. 23 Martini, N., Cliffton, E. E., and Beattie, E. J.: Survival of Lung Cancer Patients Vis-a-Vis Therapy and Cell Type, Proc. Natl. Conf. 7: 739, 1973. 24 Matthews, M., Kanhouwa, S., Pickren, J., and Robinette, D.: Frequency of Residual and Metastatic Tumor in Patients Undergoing Curative Resection for Lung Cancer, Cancer Chemother. Rep. 4: 63, 1973. 25 Mountain, C. F.: Surgical Therapy in Lung Cancer: Biologic, Physiologic and Technical Determinants, Sem. Oncol. 1: 3, 1974.
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Surgical therapy of lung cancer
26 Neuman, H. W., Ellis, F. H., and McDonald, J. R.: Bronchogenic Carcninoma in Persons Under Forty Years of Age, N. Engl. J. Med. 254: 502, 1956. 27 Paulson, D. L.: Selection of Patients for Surgery for Bronchogenic Carcinoma, Am. Surg. 39: 1, 1973. 28 Rivkin, L. M., and Salyer, J. M.: Bronchogenic Carcinoma in Men Under 40 Years of Age, Dis. Chest 34: 521, 1958. 29 Sealy, W. C : Mediastinoscopy: Does It Have a Place in the Management of Carcinoma of the Lung. Ann. Thorac. Surg. 18: 433, 1974. 30 Shields, T. W.: The Fate of Patients After Incomplete Resection of Bronchial Carcinoma, Surg. Gynecol. Obstet. 139: 569, 1974. 31 Shields T. W., Higgins, G. A., and Keehn, R. J.: Factors Influencing Survival After Resection for Bronchial Carcinoma, J. THORAC. CARDIOVASC. SURG. 64:
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32 Shields, T. W., Yee, J., Conn, J. H. and Robinette, C. D.: Relationship of Cell Type and Lymph Node Metastasis to Survival After Resection of Bronchial Carcinoma, Ann. Thorac. Surg. 20: 5, 1975. 33 Slack, N. H., Chamberlain, A., and Bross, I. D. J.: Predicting Survival Following Surgery for Bronchogenic Carcinoma, Chest: 62: 433, 1972. 34 Spjut, H. J., Roper, C. L., and Butcher, H. R.: Pulmonary Cancer and Its Prognosis, Cancer 14: 1251, 1961. 35 Weiss, W.: Operative Mortality and Five-Year Survival Rates in Men with Bronchogenic Carcinoma, Chest 66: 483, 1974. 36 Weiss, W.: Operative Mortality and Five-Year Survival Rates in Patients with Bronchogenic Carcinoma, Am. J. Surg. 128: 799 , 1974.