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The Treatment of Bronchogenic Carcinoma
The Treatnlent of Bronchogenic Carcinoma O. THERON CLAGETT JOHN W. KIRKLIN DONALD S. CHILDS, JR.
the entire period of medical knowledge of carcinoma of the lung only two methods of treatment of proved usefulness have been developed: (1) surgieal resection and (2) radiation therapy. Since Graham performed the first successful resection for a malignant pulmonary tumor just 20 years ago, it has become generally agreed that surgical removal of operable pulmonary neoplasms is the treatment of choice. Enthusiasm for radiation therapy of bronchogenic carcinoma has waxed and waned through the years. It is at present our opinion that radiation therapy is not indieated when resection can be effected but that it may be of marked palliative value in the treatment of inoperable bronchogenic careinoma. Surgieal treatment of pulmonary neoplasms has made rapid strides during the past 20 years. Operations for these lesions are based on the same principles as those for surgical treatment of carcinoma of other organs, that is, wide removal of the lesion together with the lymphatics draining the region involved. Many special problems have attended the development of surgical procedures for the removal of an organ as vital as the human lung but these problems have, to a large extent, been satisfactorily solved so that the risk of resection of the lung is now very low. It is unlikely that future developments in surgical teehnique or improvements in preoperative and postoperative care can materially improve the surgical mortality rates and resectablity rates that have been achieved . . Further improvement in the results of treatment of carcinoma of the lung by the means now available can be accomplished only by earlier diagnosis of these lesions. DURING
INCIDENCE
The 20 years that have witnessed the development of the surgical treatment of bronchogenic carcinoma have also witnessed a remarkable and alarming increase in the incidence of this malignant lesion. The ques1123
1124
O. T. Clagett, J. W. Kirklin, D. S. Childs, Jr.
tion has been raised as to whether the increasing incidence of carcinoma of the lung is only apparent or is real. Practically all the evidence available supports the conclusion that the increasing incidence of this lesion is real and is not the result of increased recognition or more accurate diagnosis. Ochsner and associates have pointed out, that from 1938 to 1948, the number of fatalities from bronchogenic carcinoma increased 144 per cent while the deaths from all types of cancer increased only 31 per cent. From 1920 to 1948, the death rate from bronchogenic carcinoma per 100,000 population increased more than ten times, from 1.1 to 11.3 per cent. The factors which may be responsible for the increasing incidence of bronchogenic carcinoma as compared to carcinoma in other organs have not been determined. Ochsner and his associates and Wynder and Graham have been ardent advocates of the theory that excessive tobacco smoking is largely responsible for the increased incidence of bronchogenic carcinoma and have collected considerable evidence in support of this thesis. Hueper has pointed out that the increasing incidence of bronchogenic carcinoma has occurred largely in the industrialized countries of the world. He suggested that carcinogenic pollutants of the air may be responsible. According to Hueper, the three main sources of potentially carcinogenic pollution of air are represented by (1) the specific hydrocarbons which are contained in the combustion and distillation products of carbonaceous matter such as oil and coal; (2) arsenicals released as fumes from metallurgical establishments and coal-burning furnaces and power plants or as dust following their use as insecticides and (3) radioactive matter presented as gases and fumes in the effluents from industrial and military radioactive operations and radioactive reaction and decay products of atomi(~ energy plants. Whatever factors are responsible for the present high incidence of bronchogenic carcinoma, this lesion has become a common one and its early diagnosis has become a major responsibility of all physicians. PATHOLOGY
A variety of primary malignant neoplasms can occur in the lung. These include adenoma of the bronchus, alveolar cell tumors, lymphoma, sarcoma and several types of primary bronchogenic carcinomas. The manifestations, clinical course, treatment and prognosis of adenomas, alveolar cell tumors, lymphomas and sarcomas of the lung are sufficiently different from those of primary bronchogenic carcinomas that they will not be ineluded in this discussion. From a considerable experience with primary bronchogenic carcinoma, we have learned that lesions can be classified into four different pathologic groups depending on the cell type that predominates. This classification is the result of a review by McDonald and his assoeiates of 849
Treatment of Bronchogenic Carcinoma
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cases of primary bronchogenic carcinoma encountered through 1948 in which the diagnosis was established at the Mayo Clinic by microscopic examination of tissue obtained by bronchoscopy or at thoracotomy. This classification of bronchogenic carcinoma has proved useful clinically. According to the pathologic criteria set up in this study of 849 cases of bronchogenic carcinoma, the incidence of the various cell types was as follows: large cell carcinoma in 40.2 per cent; squamous cell carcinoma in 37.8 per cent; adenocarcinoma in 13.2 per cent and small cell carcinoma in 8.8 per cent. CLINICAl, DATA CONCERNING LESIONS OF VAlUOUS CELL TYPES
The study of MeDonald and associates of all cases in which bronchogenic carcinoma was diagnosed at the Clinic has yielded some interesting data. Some of these data which follow include eases encountered in 1949; some do not. Large Cell Carcinoma. In 384 eases of large eell carcinoma reviewed by McDonald and associates, the youngest patient was 22 years of age, the oldest was 80 years of age and the average age was 55 years. Approximately 15 per cent of patients with large cell carcinoma were females and 85 per cent were males. Approximately 60 per cent of these tumors were located in the central portion of the lung and 40 per ('ent were peripheral. The cytologic examination of sputum or bronchial secretions for malignant cells was positive in 90 per cent of ca;.;es of this cell type of bronchogenic carcinoma when an adequate number of examinations were carried out. In this group of eases in which a diagnosis of large cell type of carcinoma of the lung was made only 49 per cent of the lesions were operated on, the remainder being too far advanced for operation at the time the diagnosis was established. Of the patients operat.ed on, resection was carried out in 57 per cent, 43 per cent proving to be inoperable at the time of exploration. Forty-three per cent of patients who survived resection lived 2 or more years after operation. Squamous Cell Carcinoma. In the series of 373 patients with squamous cell carcinoma, the youngest was 37 years of age and the oldest was 71 years of age. Approximately 95 per cent of the patients were men. Examination of sputum and bronchial secretions was positive for malignant cells in 72.4 per cent of eases in which adequate studies were carried out. The lesion was situated near the hilus in about 95 per cent of eases in which resection was performed. Exploratory thoracotomy was performed in 47.5 per cent. of cases and resection was carried out in 121 (68 per cent) .of the cases in which exploration was performed. Fifty-six per cent of patients who underwent resection were alive 2 or more years after operation, a very encouraging fact. : Adenocarcinoma. In the 112 patients with adenocarcinoma, the young~st patient was 31 years of age and the oldest was 70 years of age, with
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T. Clagett, J. W. Kirklin, D. S. Childs, Jr.
an average age of 53.3 years. Approximately 80 per cent of patients with the adenocarcinoma were males and 20 per cent females. Sixty-five per cent of the lesions for which resection was performed were located in the peripheral portions of the lung and only 35 per cent were located centrally. Cytologic examination of sputum or bronchial secretions was positive for malignant cells in 82 per cent when adequate examinations were carried out. From 1945 through 1949 there were 67 cases of adenocarcinoma of the lungs in this series. Exploratory thoracotomy was performed in 58 per cent of these patients and in 67 per cent resection was performed. Only 33.3 per cent of the patients were still alive 2 years after resection. Small Cell Carcinoma. Ninety patients in this group had a small cell type of carcinoma of the lung diagnosed by microscopie examination of tissue or by eytologie evidence. The youngest was 30 years of age, the the oldest 75 years. Approximately 97 per eent of patients with this cell type of bronehogenie eareinoma were males and only 3 per eent were females. These tumors were almost invariably located near the hilus. Cytologie examination for malignant cells was positive in more than 90 per eent of cases in whieh adequate studies were carried out. These tumors were so advanced at the time the diagnosis was made that exploratory thoraeotomy was performed in only 35 per cent of eases and reseetion was possible in only half of those in whieh exploration was performed. Of those patients on whom resection was performed, only 2 were alive 2 years after operation. Comment. The clinical significanee of this study is apparent. Squamous cell carcinoma of the lung and small cell carcinoma of the lung affect males in from 95 to 97 per cent of eases. These eell types of carcinoma tend to occur near the hilus of the lung. The squamous cell type of eareinoma of the lung is the most favorable type of bronchogenie carcinoma with regard to reseetability and prognosis. Small cell carcinoma has the poorest resectability rate and earries the poorest prognosis. Adenocarcinoma and large cell careinoma of the lung tend to occur more frequently in women than do the squamous cell and the small cell types of carcinoma of the lung. These lesions tend to occur in the peripheral rather than the hilar portion of the lung. The operability and resectability rates of adenocarcinoma are much better than those for the large cell type of carcinoma of the lung. All of these factors are of considerable importance to the surgeon since they have an important bearing on the surgical treatment of these lesions. DIAGNOSTIC CONSIDERATIONS
The diagnosis of bronchogenic carcinoma is considered in detail elsewhere in this symposium. Some remarks concerning it are nonetheless appropriate here, for effective surgical treatment of carcinoma of the lung demands early diagnosis.
Treatment of Bronchogenic Carcinoma
1127
The detection of a pulmonary lesion is not particularly difficult, since the lung is the most ac(~essible of all internal organs to ac:curate roentgenologie examination. If every man and preferably every woman between the ages of 40 and 70 years had thoracic roentgenograms taken every year, it should be possible to detect many early asymptomatic lesions of the lung, a certain number of which will inevitably be malignant. If it seems unreasonable for all individuals between the ages of 40 to 70 years to have thoracic roentgenograms made annually, it is certainly not asking too much that physicians obtain thoracic roentgenograms of all patients who have any symptoms referable to the respiratory traet and that those who have findings which even remotely suggest the possibility of carcinoma of the lung be referred for bronchoscopy, cytologic examination of the sputum and bronchial secretions for malignant cells and other definitive diagnostic studies. There is no excuse for the prolonged treatment of so-called virus pneumonias or unresolved pneumonias with antibiotics. Any patient whose pulmonary lesion does not respond promptly and completely to the antibiotic therapy that is available today should be suspected of having a carcinoma of the lung and appropriate definitive diagnostic procedures should be performed promptly. The identification, as carcinoma, of a lesion detected in the roentgenogram of the thorax poses a more difficult problem. However, if physicians everywhere would become aware of the frequency with which carcinoma of the lung occurs and would utilize the knowledge that has been accumulated regarding carcinoma of the lung, it should often be possible to identify a lesion as carcinoma in its very early stages. It is essential that the fact be recognized, however, that it is impossible to diagnose the exact pathologic nature of many pulmonary lesions even by the diagnostic methods that are available today and that exploratory thoracotomy is a necessary procedure for the diagnosis of pulmonary lesions that cannot be diagnosed by other means. Roentgenographic studies of the thorax, although extremely valuable in determining the presence and location of pulmonary lesions, cannot be expected to provide sufficient evidence for a pathologic diagnosis of the lesion that produces the roentgenologic shadow. Carcinoma of the lung can produce roentgenographic findings that simulate those of almost every other pulmonary disease. Bronchoscopic examinations are invaluable and in many instances provide accurate information regarding the location and pathologic nature of pulmonary lesions. However, only a relatively small part of the bronchial tree is accessible to bronchoscopic visualization and biopsy. A negative bronchoscopic examination does not rule out the presence of a serious pulmonary neoplasm. Cytologic examination of bronchial secretions and sputum for malignant cells has provided an :accurate preoperative diagnosis of many pulmonary carcinomas that {could not be diagnosed by any other means. However, in our experience :in approximately 25 per cent of carcinomas of the lung, the diagnosis
1128
o. T. Clagett, J. W. Kirklin, D. S.
Child.~,
Jr.
could not he established in spite of all efforts until exploratory thoracotomy had been performed. We are firmly committ,ed to the philosophy that patients with indeterminate pulmonary lesions should be advised to undergo exploratory thoracotomy. A pulmonary lesion, the nature of which cannot be diagnosed accurately and promptly before operation by the diagnostic methods that are available today, is a dangerous lesion which warrants surgical exploration. The philosophy so often pradiced of "let's wait and see what happens" is not tenable today. Doctors and not time should make the diagnosis of pulmonary disease. The risk of an exploratory thoracotomy is negligible. The risk of delay in the diagnosis of carcinoma of the lung is great. If we are to make progress in the treatment of carcinoma of the lung, it must come from earlier diagnosis of these lesions. Early diagnosis can come only from an alert medical profession which will look for can~inoma of the lung particularly in men between the ages of 40 to 70 years of age, which will use the diagnostic methods that are available early and which will encourage patients with indeterminate pulmonary lesions to undergo exploratory thoracotomy. In a recent series of 180 consecutive patients whose pulmonary lesions could not be diagnosed before operation even though every available diagnostic test was used, 30 per cent proved at operation to have brOlH"hogeni(: carcinoma. The remainder proved to have lesions whieh could only be treated or could best be treated by surgical resection. Among the lesions which proved not to be carcinoma in this series of 180 patients were 30 different pathologie pulmonary lesions. Yet all produced roentgenographic shadows suggesting the possibility of bronchogenic carcinoma. The futility of trying to establish a pathologic diagnosis on the basis of roentgenographic evidence is obvious. The fact that a pulmonary lesion discovered on routine roentgenographic examination is asymptomatic is no guarantee of its benignancy. If physicians will take advantage of their knowledge that carcinoma of the lung occurs most commonly in men between the ages of 40 and 70 and of the fact that the lung is the most accessible of all internal organs to roentgenographic study, it should be possible to detect bronchogenic carcinoma in most cases while it is still asymptomatic and to carry out surgical resection at the most effective time. SUHGICAL TREATMENT
It is generally agreed by thora(:ic surgeons that malignant neoplasms of the lung should be removed by as wide a margin as is feasible and that the resection should include the lymphatics draining the involved region. Total pneumonectomy together with an en bloc removal of the hilar and mediastinal lymph nodes is the best way of effecting this in most instances. However, the surgeon must always consider the patient
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as a whole, and not just the lesion for which operation is being performed. Many patients with carcinoma of the lung have some chronic pulmonary disability or some other relatively serious condition. Some such patients will not survive pneumoneetomy or if they do, they become respiratory cripples. On such patients with "ome pulmonary or cardiac disability, it is reasonable to perform lobeetomy rather than pneumonectomy, provided that the location of the lesion will permii it and the hilar lymph nodes are not involved with carcinoma as determined by examination of frozen sections. Fortunately, most patients tolerate pneumonectomy surpri"ingly well. Yet, it must be recognized that lobectomy has a legitimate place in the treatment of "ome carefully selected patients with carcinoma of the lung. There is not much satisfaction for either patient or surgeon in a procedure that leave" the patient seriously disabled. The results of pulmonary reseetion for carcinoma of the lung are encouraging, as has been mentioned. 4 Only in cases of small cell carcinoma of the lung are the results of reseetive treatment nearly uniformly bad. Thus, although re"ective treatment cannot ever be considered ideal, it is the only form of treatment available at present which offers hope of cure to patients with carcinoma of the lung. RADIATION THERAPY
Radiation therapy may be of marked palliative value in the treatment of inoperable bronchogenic carcinoma. Some of the effects which may be expected are: (1) relief of the obstructive pneumonitis by shrinking the obstructing bronchial lesion ; (2) relief of pain; (3) relief of cough, hemoptysis and dyspnea; (4) amelioration of symptoms due to obstruction of the superior vena cava and (5) improvement in the patient's general physical status so that he may return to work. Whether any of these beneficial effects will be noted in any particular patient cannot be predicted. In general, the more anaplastic malignant lesions will respond best to irradiation therapy. In addition, the smaller the volume of tissue which must be treated, the higher the dosage which can be given without causing severe symptoms from the radiation itself. A course of radiation therapy is arduous for the patient. In some cases, the accompanying radiation sickness and debilitating effect of the radiation may weaken the patient to such a degree that the result is detrimental rather than beneficial. Careful assessment of the patient's general physical condition, the nature and extent of the malignant process, the severity of symptoms and the pOl"sible effects of treatment on the patient should be made before embarking on a course of radiation therapy. In patients with metastasis to parts of the body outside of the chest, such as to the brain or liver, treatment to either the primary lesion or the metastatic areas is unwise unless it be given to ('ontrol severe pain. The most frequently used meam, of radiation in the control of bron-
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O. T. Clagett, .I. W. Kirklin, D. S. Childs, Jr.
chogenic caf(~inoma is externally applied roentgen rays. The rays are directed at the site of the primary lesion and the field encompasses the known extent of the disease. Frequently, anterior and posterior mediastinal portals are used and a dose of from 1,800 to 3,000 roentgens is given to the tumor in from 10 days to 3 weeks. Doses of this magnitude can be achieved easily with standard therapy machines operating in the range of from 200 to 2.50 kilovolts. Roentgen ray units operating at several million volt potentials and teletherapy units employing Co 60 as the source may prove even more efficient in delivering radiation to such tumors with minimal constitutional reactions to the patient. For small tumors which may be viewed and reached easily through a bronchoscope, direct implantation of gold radon seeds into the tumor mass may be carried out. The high radiation dosage which may be given by this means should afford a high degree of control of the local lesion. Because of the probability of metastasis or extension to the lymph nodes beyond the range of the radon seeds, external roentgen therapy should be used as supplemental therapy. For a patient who has received considerable palliation after radiation therapy but has had a recurrence of symptoms, the question of a second course of treatment comes up. It is our practice at present to give a second course of treatment if it seems likely that the patient will tolerate it. It should be remembered that in the treatment of such a disease, when palliation is the purpose, overtreatment may make the situation worse rather than better. SUMMARY
In order for treatment of bronchogenic carcinoma to be effective in a high percentage of cases, it should be instituted very early in the course of the disease. This demands a recognition of the fact that any pulmonary lesion in an adult may be cancer of the lung and that appropriate diagnostic studies must be undertaken promptly. Often, exploratory thoracotomy is the only way a diagnosis can be made in such cases. Surgical treatment in the form of pneumonectomy or occasionally lobectomy is the only type of therapy that results in a significant percentage of cures. Radiation offers considerable palliation in properly seleeted cases. REFERENCES 1. Graham, E. A. and Singer, J. J.: Successful Removal of an Entire Lung for Carcinoma of the Bronchus. J.A.M.A. 101: 1371-1374 (Oct. 28) 1933. 2. Hueper, W. C.: Air Pollution and Cancer of the Lung. Rhode Island M. J. 36: 24-30; 34; 36; 52 (Jan.) 1953. 3. Ochsner, Alton, DeCamp, P. T. and DeBakey, M. E.: Bronchogenic Carcinoma; Its Frequency, Diagnosis, and Early Treatment. J.A.M.A. 148: 691-697 (Mar. 1) 1952. 4. Symposium on the Significance of Cell Types in Bronchogenic Carcinoma: McDonald, J. R., McBurney, R. P., Carlisle, J. C. and Patton, M. M.:
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The Significance of Cell Types in Bronchogenic Carcinoma. J. Thoracic Surg. 22: 62; McBurney, R. P., McDonald, J. R. and Clagett, O. T.: Bronchogenic Small-Cell Carcinoma. 63-73; Carlisle, J. C., McDonald, J. R. and Harrington, S. W.: Bronchogenic Squamous-Cell Carcinoma. 74-82; Patton, M. M., McDonald, J. R. and Mocrsch, H. J.: Bronchogenic Adenocarcinoma. 83-87; Pattoll, M. M., McDonald, J. R. and Moersch, n. J.: Bronchogenic Large-Cell Carcinoma. 88-93 (July) 1951. 5. Wynder, E. L. and Graham, E. A.: Etiologic Factors in Bronchiogenic Carcinoma with Special Reference to Industrial Exposures; Report of Eight Hundred Fifty-seven Proved Cases. Arch. Indust. Hyg. 4: 221-235 (Sept.) 1951.
the entire period of medical knowledge of carcinoma of the lung only two methods of treatment of proved usefulness have been developed: (1) surgieal resection and (2) radiation therapy. Since Graham performed the first successful resection for a malignant pulmonary tumor just 20 years ago, it has become generally agreed that surgical removal of operable pulmonary neoplasms is the treatment of choice. Enthusiasm for radiation therapy of bronchogenic carcinoma has waxed and waned through the years. It is at present our opinion that radiation therapy is not indieated when resection can be effected but that it may be of marked palliative value in the treatment of inoperable bronchogenic careinoma. Surgieal treatment of pulmonary neoplasms has made rapid strides during the past 20 years. Operations for these lesions are based on the same principles as those for surgical treatment of carcinoma of other organs, that is, wide removal of the lesion together with the lymphatics draining the region involved. Many special problems have attended the development of surgical procedures for the removal of an organ as vital as the human lung but these problems have, to a large extent, been satisfactorily solved so that the risk of resection of the lung is now very low. It is unlikely that future developments in surgical teehnique or improvements in preoperative and postoperative care can materially improve the surgical mortality rates and resectablity rates that have been achieved . . Further improvement in the results of treatment of carcinoma of the lung by the means now available can be accomplished only by earlier diagnosis of these lesions. DURING
INCIDENCE
The 20 years that have witnessed the development of the surgical treatment of bronchogenic carcinoma have also witnessed a remarkable and alarming increase in the incidence of this malignant lesion. The ques1123
1124
O. T. Clagett, J. W. Kirklin, D. S. Childs, Jr.
tion has been raised as to whether the increasing incidence of carcinoma of the lung is only apparent or is real. Practically all the evidence available supports the conclusion that the increasing incidence of this lesion is real and is not the result of increased recognition or more accurate diagnosis. Ochsner and associates have pointed out, that from 1938 to 1948, the number of fatalities from bronchogenic carcinoma increased 144 per cent while the deaths from all types of cancer increased only 31 per cent. From 1920 to 1948, the death rate from bronchogenic carcinoma per 100,000 population increased more than ten times, from 1.1 to 11.3 per cent. The factors which may be responsible for the increasing incidence of bronchogenic carcinoma as compared to carcinoma in other organs have not been determined. Ochsner and his associates and Wynder and Graham have been ardent advocates of the theory that excessive tobacco smoking is largely responsible for the increased incidence of bronchogenic carcinoma and have collected considerable evidence in support of this thesis. Hueper has pointed out that the increasing incidence of bronchogenic carcinoma has occurred largely in the industrialized countries of the world. He suggested that carcinogenic pollutants of the air may be responsible. According to Hueper, the three main sources of potentially carcinogenic pollution of air are represented by (1) the specific hydrocarbons which are contained in the combustion and distillation products of carbonaceous matter such as oil and coal; (2) arsenicals released as fumes from metallurgical establishments and coal-burning furnaces and power plants or as dust following their use as insecticides and (3) radioactive matter presented as gases and fumes in the effluents from industrial and military radioactive operations and radioactive reaction and decay products of atomi(~ energy plants. Whatever factors are responsible for the present high incidence of bronchogenic carcinoma, this lesion has become a common one and its early diagnosis has become a major responsibility of all physicians. PATHOLOGY
A variety of primary malignant neoplasms can occur in the lung. These include adenoma of the bronchus, alveolar cell tumors, lymphoma, sarcoma and several types of primary bronchogenic carcinomas. The manifestations, clinical course, treatment and prognosis of adenomas, alveolar cell tumors, lymphomas and sarcomas of the lung are sufficiently different from those of primary bronchogenic carcinomas that they will not be ineluded in this discussion. From a considerable experience with primary bronchogenic carcinoma, we have learned that lesions can be classified into four different pathologic groups depending on the cell type that predominates. This classification is the result of a review by McDonald and his assoeiates of 849
Treatment of Bronchogenic Carcinoma
1125
cases of primary bronchogenic carcinoma encountered through 1948 in which the diagnosis was established at the Mayo Clinic by microscopic examination of tissue obtained by bronchoscopy or at thoracotomy. This classification of bronchogenic carcinoma has proved useful clinically. According to the pathologic criteria set up in this study of 849 cases of bronchogenic carcinoma, the incidence of the various cell types was as follows: large cell carcinoma in 40.2 per cent; squamous cell carcinoma in 37.8 per cent; adenocarcinoma in 13.2 per cent and small cell carcinoma in 8.8 per cent. CLINICAl, DATA CONCERNING LESIONS OF VAlUOUS CELL TYPES
The study of MeDonald and associates of all cases in which bronchogenic carcinoma was diagnosed at the Clinic has yielded some interesting data. Some of these data which follow include eases encountered in 1949; some do not. Large Cell Carcinoma. In 384 eases of large eell carcinoma reviewed by McDonald and associates, the youngest patient was 22 years of age, the oldest was 80 years of age and the average age was 55 years. Approximately 15 per cent of patients with large cell carcinoma were females and 85 per cent were males. Approximately 60 per cent of these tumors were located in the central portion of the lung and 40 per ('ent were peripheral. The cytologic examination of sputum or bronchial secretions for malignant cells was positive in 90 per cent of ca;.;es of this cell type of bronchogenic carcinoma when an adequate number of examinations were carried out. In this group of eases in which a diagnosis of large cell type of carcinoma of the lung was made only 49 per cent of the lesions were operated on, the remainder being too far advanced for operation at the time the diagnosis was established. Of the patients operat.ed on, resection was carried out in 57 per cent, 43 per cent proving to be inoperable at the time of exploration. Forty-three per cent of patients who survived resection lived 2 or more years after operation. Squamous Cell Carcinoma. In the series of 373 patients with squamous cell carcinoma, the youngest was 37 years of age and the oldest was 71 years of age. Approximately 95 per cent of the patients were men. Examination of sputum and bronchial secretions was positive for malignant cells in 72.4 per cent of eases in which adequate studies were carried out. The lesion was situated near the hilus in about 95 per cent of eases in which resection was performed. Exploratory thoracotomy was performed in 47.5 per cent. of cases and resection was carried out in 121 (68 per cent) .of the cases in which exploration was performed. Fifty-six per cent of patients who underwent resection were alive 2 or more years after operation, a very encouraging fact. : Adenocarcinoma. In the 112 patients with adenocarcinoma, the young~st patient was 31 years of age and the oldest was 70 years of age, with
1126
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an average age of 53.3 years. Approximately 80 per cent of patients with the adenocarcinoma were males and 20 per cent females. Sixty-five per cent of the lesions for which resection was performed were located in the peripheral portions of the lung and only 35 per cent were located centrally. Cytologic examination of sputum or bronchial secretions was positive for malignant cells in 82 per cent when adequate examinations were carried out. From 1945 through 1949 there were 67 cases of adenocarcinoma of the lungs in this series. Exploratory thoracotomy was performed in 58 per cent of these patients and in 67 per cent resection was performed. Only 33.3 per cent of the patients were still alive 2 years after resection. Small Cell Carcinoma. Ninety patients in this group had a small cell type of carcinoma of the lung diagnosed by microscopie examination of tissue or by eytologie evidence. The youngest was 30 years of age, the the oldest 75 years. Approximately 97 per eent of patients with this cell type of bronehogenie eareinoma were males and only 3 per eent were females. These tumors were almost invariably located near the hilus. Cytologie examination for malignant cells was positive in more than 90 per eent of cases in whieh adequate studies were carried out. These tumors were so advanced at the time the diagnosis was made that exploratory thoraeotomy was performed in only 35 per cent of eases and reseetion was possible in only half of those in whieh exploration was performed. Of those patients on whom resection was performed, only 2 were alive 2 years after operation. Comment. The clinical significanee of this study is apparent. Squamous cell carcinoma of the lung and small cell carcinoma of the lung affect males in from 95 to 97 per cent of eases. These eell types of carcinoma tend to occur near the hilus of the lung. The squamous cell type of eareinoma of the lung is the most favorable type of bronchogenie carcinoma with regard to reseetability and prognosis. Small cell carcinoma has the poorest resectability rate and earries the poorest prognosis. Adenocarcinoma and large cell careinoma of the lung tend to occur more frequently in women than do the squamous cell and the small cell types of carcinoma of the lung. These lesions tend to occur in the peripheral rather than the hilar portion of the lung. The operability and resectability rates of adenocarcinoma are much better than those for the large cell type of carcinoma of the lung. All of these factors are of considerable importance to the surgeon since they have an important bearing on the surgical treatment of these lesions. DIAGNOSTIC CONSIDERATIONS
The diagnosis of bronchogenic carcinoma is considered in detail elsewhere in this symposium. Some remarks concerning it are nonetheless appropriate here, for effective surgical treatment of carcinoma of the lung demands early diagnosis.
Treatment of Bronchogenic Carcinoma
1127
The detection of a pulmonary lesion is not particularly difficult, since the lung is the most ac(~essible of all internal organs to ac:curate roentgenologie examination. If every man and preferably every woman between the ages of 40 and 70 years had thoracic roentgenograms taken every year, it should be possible to detect many early asymptomatic lesions of the lung, a certain number of which will inevitably be malignant. If it seems unreasonable for all individuals between the ages of 40 to 70 years to have thoracic roentgenograms made annually, it is certainly not asking too much that physicians obtain thoracic roentgenograms of all patients who have any symptoms referable to the respiratory traet and that those who have findings which even remotely suggest the possibility of carcinoma of the lung be referred for bronchoscopy, cytologic examination of the sputum and bronchial secretions for malignant cells and other definitive diagnostic studies. There is no excuse for the prolonged treatment of so-called virus pneumonias or unresolved pneumonias with antibiotics. Any patient whose pulmonary lesion does not respond promptly and completely to the antibiotic therapy that is available today should be suspected of having a carcinoma of the lung and appropriate definitive diagnostic procedures should be performed promptly. The identification, as carcinoma, of a lesion detected in the roentgenogram of the thorax poses a more difficult problem. However, if physicians everywhere would become aware of the frequency with which carcinoma of the lung occurs and would utilize the knowledge that has been accumulated regarding carcinoma of the lung, it should often be possible to identify a lesion as carcinoma in its very early stages. It is essential that the fact be recognized, however, that it is impossible to diagnose the exact pathologic nature of many pulmonary lesions even by the diagnostic methods that are available today and that exploratory thoracotomy is a necessary procedure for the diagnosis of pulmonary lesions that cannot be diagnosed by other means. Roentgenographic studies of the thorax, although extremely valuable in determining the presence and location of pulmonary lesions, cannot be expected to provide sufficient evidence for a pathologic diagnosis of the lesion that produces the roentgenologic shadow. Carcinoma of the lung can produce roentgenographic findings that simulate those of almost every other pulmonary disease. Bronchoscopic examinations are invaluable and in many instances provide accurate information regarding the location and pathologic nature of pulmonary lesions. However, only a relatively small part of the bronchial tree is accessible to bronchoscopic visualization and biopsy. A negative bronchoscopic examination does not rule out the presence of a serious pulmonary neoplasm. Cytologic examination of bronchial secretions and sputum for malignant cells has provided an :accurate preoperative diagnosis of many pulmonary carcinomas that {could not be diagnosed by any other means. However, in our experience :in approximately 25 per cent of carcinomas of the lung, the diagnosis
1128
o. T. Clagett, J. W. Kirklin, D. S.
Child.~,
Jr.
could not he established in spite of all efforts until exploratory thoracotomy had been performed. We are firmly committ,ed to the philosophy that patients with indeterminate pulmonary lesions should be advised to undergo exploratory thoracotomy. A pulmonary lesion, the nature of which cannot be diagnosed accurately and promptly before operation by the diagnostic methods that are available today, is a dangerous lesion which warrants surgical exploration. The philosophy so often pradiced of "let's wait and see what happens" is not tenable today. Doctors and not time should make the diagnosis of pulmonary disease. The risk of an exploratory thoracotomy is negligible. The risk of delay in the diagnosis of carcinoma of the lung is great. If we are to make progress in the treatment of carcinoma of the lung, it must come from earlier diagnosis of these lesions. Early diagnosis can come only from an alert medical profession which will look for can~inoma of the lung particularly in men between the ages of 40 to 70 years of age, which will use the diagnostic methods that are available early and which will encourage patients with indeterminate pulmonary lesions to undergo exploratory thoracotomy. In a recent series of 180 consecutive patients whose pulmonary lesions could not be diagnosed before operation even though every available diagnostic test was used, 30 per cent proved at operation to have brOlH"hogeni(: carcinoma. The remainder proved to have lesions whieh could only be treated or could best be treated by surgical resection. Among the lesions which proved not to be carcinoma in this series of 180 patients were 30 different pathologie pulmonary lesions. Yet all produced roentgenographic shadows suggesting the possibility of bronchogenic carcinoma. The futility of trying to establish a pathologic diagnosis on the basis of roentgenographic evidence is obvious. The fact that a pulmonary lesion discovered on routine roentgenographic examination is asymptomatic is no guarantee of its benignancy. If physicians will take advantage of their knowledge that carcinoma of the lung occurs most commonly in men between the ages of 40 and 70 and of the fact that the lung is the most accessible of all internal organs to roentgenographic study, it should be possible to detect bronchogenic carcinoma in most cases while it is still asymptomatic and to carry out surgical resection at the most effective time. SUHGICAL TREATMENT
It is generally agreed by thora(:ic surgeons that malignant neoplasms of the lung should be removed by as wide a margin as is feasible and that the resection should include the lymphatics draining the involved region. Total pneumonectomy together with an en bloc removal of the hilar and mediastinal lymph nodes is the best way of effecting this in most instances. However, the surgeon must always consider the patient
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as a whole, and not just the lesion for which operation is being performed. Many patients with carcinoma of the lung have some chronic pulmonary disability or some other relatively serious condition. Some such patients will not survive pneumoneetomy or if they do, they become respiratory cripples. On such patients with "ome pulmonary or cardiac disability, it is reasonable to perform lobeetomy rather than pneumonectomy, provided that the location of the lesion will permii it and the hilar lymph nodes are not involved with carcinoma as determined by examination of frozen sections. Fortunately, most patients tolerate pneumonectomy surpri"ingly well. Yet, it must be recognized that lobectomy has a legitimate place in the treatment of "ome carefully selected patients with carcinoma of the lung. There is not much satisfaction for either patient or surgeon in a procedure that leave" the patient seriously disabled. The results of pulmonary reseetion for carcinoma of the lung are encouraging, as has been mentioned. 4 Only in cases of small cell carcinoma of the lung are the results of reseetive treatment nearly uniformly bad. Thus, although re"ective treatment cannot ever be considered ideal, it is the only form of treatment available at present which offers hope of cure to patients with carcinoma of the lung. RADIATION THERAPY
Radiation therapy may be of marked palliative value in the treatment of inoperable bronchogenic carcinoma. Some of the effects which may be expected are: (1) relief of the obstructive pneumonitis by shrinking the obstructing bronchial lesion ; (2) relief of pain; (3) relief of cough, hemoptysis and dyspnea; (4) amelioration of symptoms due to obstruction of the superior vena cava and (5) improvement in the patient's general physical status so that he may return to work. Whether any of these beneficial effects will be noted in any particular patient cannot be predicted. In general, the more anaplastic malignant lesions will respond best to irradiation therapy. In addition, the smaller the volume of tissue which must be treated, the higher the dosage which can be given without causing severe symptoms from the radiation itself. A course of radiation therapy is arduous for the patient. In some cases, the accompanying radiation sickness and debilitating effect of the radiation may weaken the patient to such a degree that the result is detrimental rather than beneficial. Careful assessment of the patient's general physical condition, the nature and extent of the malignant process, the severity of symptoms and the pOl"sible effects of treatment on the patient should be made before embarking on a course of radiation therapy. In patients with metastasis to parts of the body outside of the chest, such as to the brain or liver, treatment to either the primary lesion or the metastatic areas is unwise unless it be given to ('ontrol severe pain. The most frequently used meam, of radiation in the control of bron-
1130
O. T. Clagett, .I. W. Kirklin, D. S. Childs, Jr.
chogenic caf(~inoma is externally applied roentgen rays. The rays are directed at the site of the primary lesion and the field encompasses the known extent of the disease. Frequently, anterior and posterior mediastinal portals are used and a dose of from 1,800 to 3,000 roentgens is given to the tumor in from 10 days to 3 weeks. Doses of this magnitude can be achieved easily with standard therapy machines operating in the range of from 200 to 2.50 kilovolts. Roentgen ray units operating at several million volt potentials and teletherapy units employing Co 60 as the source may prove even more efficient in delivering radiation to such tumors with minimal constitutional reactions to the patient. For small tumors which may be viewed and reached easily through a bronchoscope, direct implantation of gold radon seeds into the tumor mass may be carried out. The high radiation dosage which may be given by this means should afford a high degree of control of the local lesion. Because of the probability of metastasis or extension to the lymph nodes beyond the range of the radon seeds, external roentgen therapy should be used as supplemental therapy. For a patient who has received considerable palliation after radiation therapy but has had a recurrence of symptoms, the question of a second course of treatment comes up. It is our practice at present to give a second course of treatment if it seems likely that the patient will tolerate it. It should be remembered that in the treatment of such a disease, when palliation is the purpose, overtreatment may make the situation worse rather than better. SUMMARY
In order for treatment of bronchogenic carcinoma to be effective in a high percentage of cases, it should be instituted very early in the course of the disease. This demands a recognition of the fact that any pulmonary lesion in an adult may be cancer of the lung and that appropriate diagnostic studies must be undertaken promptly. Often, exploratory thoracotomy is the only way a diagnosis can be made in such cases. Surgical treatment in the form of pneumonectomy or occasionally lobectomy is the only type of therapy that results in a significant percentage of cures. Radiation offers considerable palliation in properly seleeted cases. REFERENCES 1. Graham, E. A. and Singer, J. J.: Successful Removal of an Entire Lung for Carcinoma of the Bronchus. J.A.M.A. 101: 1371-1374 (Oct. 28) 1933. 2. Hueper, W. C.: Air Pollution and Cancer of the Lung. Rhode Island M. J. 36: 24-30; 34; 36; 52 (Jan.) 1953. 3. Ochsner, Alton, DeCamp, P. T. and DeBakey, M. E.: Bronchogenic Carcinoma; Its Frequency, Diagnosis, and Early Treatment. J.A.M.A. 148: 691-697 (Mar. 1) 1952. 4. Symposium on the Significance of Cell Types in Bronchogenic Carcinoma: McDonald, J. R., McBurney, R. P., Carlisle, J. C. and Patton, M. M.:
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The Significance of Cell Types in Bronchogenic Carcinoma. J. Thoracic Surg. 22: 62; McBurney, R. P., McDonald, J. R. and Clagett, O. T.: Bronchogenic Small-Cell Carcinoma. 63-73; Carlisle, J. C., McDonald, J. R. and Harrington, S. W.: Bronchogenic Squamous-Cell Carcinoma. 74-82; Patton, M. M., McDonald, J. R. and Mocrsch, H. J.: Bronchogenic Adenocarcinoma. 83-87; Pattoll, M. M., McDonald, J. R. and Moersch, n. J.: Bronchogenic Large-Cell Carcinoma. 88-93 (July) 1951. 5. Wynder, E. L. and Graham, E. A.: Etiologic Factors in Bronchiogenic Carcinoma with Special Reference to Industrial Exposures; Report of Eight Hundred Fifty-seven Proved Cases. Arch. Indust. Hyg. 4: 221-235 (Sept.) 1951.