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PNEUMONECTOMY AND LOBECTOMY IN BRONCHOGENIC CARCINOMA
PNEUMONECTOMY A N D
LOBECTOMY
I N BRONCHOGENIC CARCINOMA A Comparison of End Results of the Overholt and Ochsner Clinics M. B. Shimkin, M.D., R. R. Connelly, B.S., S. C. Marcus; B.S.,* and S. J. Cutler, Sc.D., Bethesda,
Md.
T
HERE is general agreement that surgical resection is the only curative thera peutic modality in bronchogenic cancer. There is no general agreement, however, regarding the type of resection that should be carried out. Some thoracic surgeons recommend the radical pneumonectomy with en bloc mediastinal lymph node dissection, whereas other centers carry out more limited pro cedures, such as lobectomy, with such mediastinal lymph node dissection as the exposure allows. A typical exchange of views on this subject followed the presentation of the paper by Overholt and Bougas 1 in 1956. These differences of opinion among surgeons remain unresolved. A summary of 10 large series encompassing 7,868 patients with bronchogenic carcinoma2 demonstrated the following features: (1) of those in whom diagnosis is made, just over 50 per cent undergo thoracotomy; (2) in those who have exploratory operations, approximately 60 per cent of the lesions are found to be resectable; and (3) the 5-year survival in all cases is under 10 per cent, and approximately 20 per cent in patients with resectable lesions. There are no publications on acceptably comparable groups of patients treated by pneumonec tomy and by lobectomy to indicate the relative merits of the two types of opera tion. However, there is evidence that postoperative mortality and morbidity are higher among patients subjected to the more extensive resection. 2 ' 3 Definitive comparison between pneumonectomy and lobectomy for bron chogenic carcinoma requires carefully planned and executed clinical trials that would include random assignment of patients to the treatment groups being compared. In the absence of data from such trials, sources of information for comparing the results of lobectomy and pneumonectomy are limited to selected surgical centers with different policies of treatment. At the second workshop on lung cancer research sponsored by the American Cancer Society and held at Arden House on February 27 to March 1, 1959, it was suggested that a more systematic analytical comparison of available data
D. C.
From the National Cancer Institute, Bethesda, Md. Received for publication Jan. 2, 1962. ♦Present address: Division of Air Pollution, U. S. Public H.-alth Service, Washington, 503
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would be desirable. As a result, Dr. Alton Ochsner of New Orleans, who has consistently espoused pneumonectomy for lung cancer, and Dr. Richard H. Overholt of Boston, who during more recent years has tended to use lobectomy as the treatment of choice, agreed to permit the Biometry Branch of the National Cancer Institute to compare the survival of their surgically treated patients. A protocol followed in abstracting information on patients with lung cancer, developed by the End Results Group of the National Cancer Institute, was modified for this purpose. We are greatly indebted to Dr. Ochsner and to Dr. Overholt for their full cooperation in making all necessary records available for abstracting. The analyses and interpretations of their data are the responsibility of the authors, and were prepared independently of the surgeons involved. The manuscript in its completed form, of course, was seen by Drs. Ochsner and Overholt, who corrected errors of fact and expressed their opinions of the analysis. The report is thus published with their knowledge. Such knowledge does not necessarily imply either approval or agreement by either or both surgeons. GENERAL N A T U R E OF DATA
Overholt Data.— At the Overholt Thoracic Clinic, there has been a shift in policy from pneumonectomy to lobectomy as the treatment of choice for bronchogenic cancer. During the period selected for study, 1951-1956, the proportion of lobectomies among the resections increased from 20 per cent in 1951 to 45 per cent during 1955-1956. Dr. Overholt described current practice as follows,4 " O n explora tion, the uppermost lymph node is removed from the mediastinum and examined histologically; all visible lymph nodes are resected whether one is doing a lobectomy or a pneumonectomy. . . . The extent of research depends on the extent of the tumor. . . . I see no reason to take out an entire lung when a person has a very small localized cancer in one lobe, particularly where lymph nodes are negative." During the period of shift toward preservation of pulmonary tissue, a more aggressive approach has been evident toward the management of the lymph nodes. During 1951-1954, mediastinal lymph nodes were resected in 40 per cent of the "pneumonectomies" and in 18 per cent of the "lobectomies." During 1955-1956, mediastinal lymph node resection was carried out in 94 per cent of the "pneumonectomies" and in 56 per cent of the "lobectomies." The over-all experience at the Overholt Clinic was summarized by Overholt and Bougas in 1956.1 During the period 1941-1955, 1,237 patients with pri mary lung cancer were seen. Of these, 64 per cent .were explored and in 65 per cent of those explored, or in 42 per cent of the total, resections were per formed. The study group from the Overholt Clinic consisted of the 331 surgicallytreated patients with primary carcinoma of the lung, diagnosed during the years 1951-1956, inclusive. Four of these cases were excluded from this study. Two patients were operated upon elsewhere by surgeons not on the Overholt
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staff. Another patient, diagnosed elsewhere and considered inoperable, did not undergo operation until 9 months after diagnosis. The fourth case was excluded because the resected tumor later proved to be a metastasis from carcinoma of the bladder. Thus, 327 patients surgically treated by Dr. Diehard Overholt or members of his staff were included in this analysis. Of these, 211 were classified as "pneumonectomies" and 116 as "lobectomies." However, the Overholt "pneumonectomy" group includes 89 patients in whom systematic mediastinal lymph node resection was not carried out. Under the designation of "lobectomy," 75 patients did not have a mediastinal lymph node resection. This group also includes 14 patients in whom two lobes of the right lung were removed, and 4 patients in whom the operation was limited to a segmental resection. In one patient, lobectomy was followed by a segmental resection on the opposite side 2 weeks later for a bilateral lesion. At the Overholt Clinic, the primary treatment for lung cancer was limited to surgery in 80 per cent of the "pneumonectomies" and in 93 per cent of the "lobectomies." X-ray treatment was employed in 41 cases of pneumonectomy (19 per cent) and in 7 cases of lobectomy (6 per cent). Only 2 patients re ceived adjuvant chemotherapy (nitrogen mustard) following pneumonectomy as part of their primary treatment, and one patient received both x-ray and chemotherapy following lobectomy. Ochsner Data.— The following statement by Dr. Ochsner reflects the surgical procedure that is followed at the Ochsner Clinic.5 "Although it has been advocated by some that lobectomy may be used in the treatment of bronchogenic cancer and although certain patients with cancer of the bronchus can be cured by lobectomy, we are convinced that lobectomy is not a good cancer operation and should not be used except in the patient in whom careful preoperative pulmonary function studies indicate that the patient cannot tolerate a pneumonectomy." This policy is reflected in the fact that over 90 per cent of resections for lung cancer were pneumonectomies during the period selected for study, 1948-1956, and lobectomy was reserved for patients who were considered unable to tolerate more extensive surgical procedure. In 1960, Ochsner and his associates6 summarized the total experience at the Ochsner Clinic and Foundation Hospital from 1942 to 1957 as follows: There were 875 cases of primary lung cancer, in which 525 of the patients were explored (60 per cent). Kesection was performed in 356 patients, who con stituted 68 per cent of the cases of exploration, or 41 per cent of the total cases. The study group from the Ochsner Clinic consisted of the 205 patients who were subjected to resection during the period 1948-1956, inclusive. The 3 earlier years, 1948-1950, not represented in the Overholt series, were included in order to increase the pneumonectomy series to approximately the same number as in the Overholt group. Deletion of these cases would not alter or modify significantly any of the findings. One case was excluded from this analysis; this patient had had a lobectomy elsewhere and the resection was extended at the Ochsner Clinic several months later.
TABLE I .
LOBECTOMY MONTHS AFTER OPERA TION 0.0- 0.9 1.0- 1.9 2.0- 2.9 3.0- 3.9 4.0- 4.9 5.0- 5.9 6.0- 8.9 9.0-11.9 12.0-17.9 18.0-23.9 24.0-29.9 30.0-35.9 36.0-41.9 42.0-47.9 48.0-53.9 54.0-59.9 60.0 +
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ALIVE AT BEGINNING OF INTERVAL 116 103 98 96 93 87 83 75 65 54 44 42 36 34 26 20 14
DIED DURING INTERVAL 13 5 2 3 6 4 8 10 11 10 2 2 1 2 1 2
DETAILED L I F E TABLE ANALYSIS BY OPERATION: OCHSNER CLINIC, 1948-1956;
(OVERHOLT) ALIVE AT LAST CONTACT* WITH DRAWN LOST
_ -
-
2
2 1 5 5 4
1
-
PNEUMONECTOMY PERCENT ALIVE AT END OF INTERVAL 89 84 83 80 75 72 65 56 47 38 36 34 33 31 30 27
ALIVE AT BEGINNING OF INTERVAL 211 183 165 154 150 142 131 110 95 75 64 51 44 37 33 28 27
DIED DURING INTERVAL 26 16 11 4 8 11 21 15 19 11 12 4 3 1 3
-
*If date of last contact was earlier than 1959, classified as "lost" to follow-up; if 1959 or
Only 13 of the 204 Ochsner patients were treated by lobectomy, one by a segmental resection and one by right bilobectomy. Pulmonary or cardiac function studies indicated that only a lobectomy could be tolerated by 10 of these patients. In 3 other patients a pneumonectomy seemed contraindicated because of invasion of tumor beyond the thorax. Four patients at the Ochsner Clinic underwent a lobectomy which was followed in 4 to 21 days by complete removal of the remaining lung tissue on the same side. These patients were classified as "pneumonectomies." The term "pneumonectomy" at the Ochsner Clinic covers an operation performed somewhat differently from that at the Overholt Clinic. At the Ochsner Clinic, where pneumonectomy is the treatment of choice, the standard procedure is the removal of the entire involved lung with an en bloc excision of the mediastinal nodes. This policy is reflected in the present series. In only 10 of the 191 Ochsner "pneumonectomies" were the mediastinal nodes not removed. At the Ochsner Clinic, 65 per cent of the patients who underwent a pneu monectomy received no adjuvant therapy. In 35 per cent, the primary treat ment included the addition of x-ray therapy (3 per cent), chemotherapy with nitrogen mustard 27 per cent), or both (5 per cent). The injections of nitrogen mustard were often repeated during the subsequent course of treatment. Total Data.— For the main analysis, therefore, there were available three main groups of patients treated surgically for primary lung cancer: (1) Overholt "pneu monectomies," 211 patients; of these, 122 (58 per cent) had mediastinal lymph node dissection as part of the operation; (2) Overholt "lobectomies," 116 pa tients; of these, 41 (35 per cent) had mediastinal lymph node resection as the
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BRONCHOGENIC CARCINOMA
SURGICALLY TREATED L U N G CANCER PATIENTS OVERHOLT CLINIC, 1951-1956 (OVERHOLT) ALIVE AT LAST CONTACT* WITH LOST DRAWN
-
1 3 2 3 2 1
■
PERCENT ALIVE AT END OF INTERVAL 88 80 75 73 69 63 53 46 37 31 25 23 22 21 19 19
ALIVE A T BEGINNING OF INTERVAL 191 156 145 133 128 114 102 86 76 52 44 38 38 33 29 26 21
PNEUMONECTOMY (OCHSNER) ALIVE AT LAST CONTACT* WITH DIED DURING LOST DRAWN INTERVAL 35 11 12 5 14 12 16 10 24 8 6 0 4 1 1 2
_ _ _ _ 1 3 2 3
PERCENT ALIVE AT END OF INTERVAL 82 76 70 67 60 53 45 40 27 23 20 20 18 17 17 15
later, classified as "withdrawn" alive.
exposure allowed; and (3) Ochsner "pneumonectomies," 191 patients; of these, 181 (95 per cent) had mediastinal lymph node dissection, usually en bloc with the lung. The 13 Ochsner " lobectomies" occurred in a selected group of patients, as previously mentioned. There were no postoperative deaths in the 13 cases and 6 survived the first year, but there were no 5-year survivors. This group was considered too small for more definitive analysis, and was excluded in the sub sequent presentation. Inclusion of these cases in the Ochsner series would not affect any of the conclusions and interpretations. STATISTICAL ANALYSES
The observed survival rates reported in this study were computed using the actuarial or life-table method as described by Cutler and Ederer. 7 While only the 5-year rates are presented in the subsequent analyses, they were obtained from life-table analyses as detailed as those shown in Table I. All rates were computed using the length of survival from first definitive surgery to the date of last contact. Follow-up information at both clinics was excellent. Only 10 of 327 pa tients were classified as lost to follow-up at the Overholt Clinic, and there were no losses to follow-up among the 204 Ochsner cases. A lost case was defined as any patient alive at last contact but not followed at least into calendar year 1959. Patients lost to follow-up were not excluded from the study. Rather, they were entered in the life-table analysis as patients under observation from the date of surgery to the date last known to be alive. In effect this means that subsequent to the date of last contact, lost patients were assumed to have
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experienced a survival pattern similar to the patients who remained under follow-up study. Only observed cumulative survival rates are presented in this paper. Ex tending the analysis to include relative survival rates, which adjust the observed survival rates for normal life expectancy, was considered. Using appropriate Massachusetts and Louisiana State life tables, the 5-year expected survival rates corresponding to the age and sex distributions among lobectomy and pneumonectomy groups at the Overholt Clinic and the pneumonectomy group at the Ochsner Clinic were 85, 87, and 88 per cent, respectively. In view of the small differences among the expected survival rates, relationships among the three treatment groups, based on observed survival rates, are almost identical with those based on relative rates. It was, therefore, decided to restrict the presentation to the observed rates, except in the analysis of the association of age and survival. All conclusions in which significant differences between groups are claimed meet appropriate statistical criteria. The level of significance used in all the tests mentioned below was P = 0.05. Thus, an observed difference was ac cepted as statistically significant, if the probability that a difference at least as large as would occur by chance alone was 5 per cent or less. The " t " test was used in testing differences between average ages and average size of lesion, and for testing differences between survival rates. The standard error of a survival rate was computed according to the formula developed by Greenwood. The X2 test for independence was used in comparing the distribution of cases with respect to histologic type, size and location of lesion, and age. RESULTS
The survival experience of the three surgically-treated groups is presented, in the form of a detailed life table, in Table I. The 5-year survival rate was definitely higher for patients treated by the Overholt lobectomy (27 per cent) than for patients treated by pneumonectomy (19 per cent at the Overholt Clinic and 15 per cent at the Ochsner Clinic). All deaths within the first 30 days following operation were classified as operative deaths. At the Overholt Clinic, postoperative mortality was 11 per cent in the lobectomy group and 12 per cent in the pneumonectomy group. Among patients treated by the Ochsner pneumonectomy, postoperative mortality was 18 per cent. Exclusion of postoperative deaths has no significant effect on the relationship of the survival rates for the three operation groups. For ex ample, excluding postoperative deaths, the 5-year survival rates were 30 per cent for the Overholt lobectomy group, 22 per cent for the Overholt pneumonec tomy group, and 19 per cent for the Ochsner pneumonectomy group. These rates compare with rates of 27, 19, and 15 per cent based on all cases of resec tion. All survival rates presented in the discussion that follows include the effect of postoperative mortality. As in all comparisons of results of different procedures and different clinics, the conclusions are valid only to the degree that appropriate considera-
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tion can be made for the various factors of selection that were involved. The question of comparability can be answered only partially in any study not specifically designed to avoid conscious or unintended selection. Nevertheless, it is useful to consider some known factors in order to reveal differences due to selection that can be adjusted for their effects on survival, and to indicate the similarities, and differences among the patients and their disease in the groups that are being compared. The following variables were therefore analyzed: in respect to the neoplasmits extent, its size, location in the lung, and its histologic type; in respect to other treatment-the effect of mediastinal lymph node dissection and of adjuvant x-ray or nitrogen mustard therapy; in respect to the patient-the effect of age and of sex. ANALYSIS OF VARIABLES
Extent of Disease.—The anatomical extent of involvement by a neoplasm is probably the single most important determinant of prognosis. The end results thus inevitably reflect the proportion of patients that enter a series at the localized and more advanced stages of the disease. The three groups of patients under analysis were classified into two stage categories. The "localized" cases were those in which the tumor was confined to the lung or bronchus, and in which the pathologist found no direct extension to neighboring tissues or metastasis to the resected lymph nodes. The "not-localized" cases were those in which there were regional lymph node metastases or extension of the tumor beyond the lung. Also included in this categogory were some patients with evidence of distant spread or distant metastases who nevertheless had pulmonary resections. TABLE I I .
FIVE-YEAR SURVIVAL RATES BY STAGE OF D I S E A S E AND OPERATION: SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY
( OVERHOLT)
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE STAGE o r
DISEASE
Localized Not localized Regional Distant Total, all stages
NO.
%
60 52 56 48 (48) (41) (7) (8) 116 100
(%) 40 12 (14) (0) 27
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
45 21 166 79 (143) (68) (23) (11) 211 100
(%) 35 15 (16) (0) 19
5-YEAR SURVIVAL RATE NO.
%
49 26 142 74 (138) (72) (4) (2) 191 100
(%) 39 7 (7) (0) 15
In Table II, the patients in each of the three treatment groups are classified according to extent of disease, and the 5-year survival rate for each subgroup is given. I t is immediately apparent that the proportion of the more favorable, localized cases is highest in the Overholt lobectomy group, 52 per cent, in con trast with 21 and 26 per cent in the Overholt pneumonectomy and the Ochsner pneumonectomy groups, respectively. It is thus evident that a major factor in the better survival following lobectomy, as seen in Table I, is the greater pro-
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portion of patients with localized tumors that were selected for lobectomy. If the data for both Overholt groups are combined, the proportion of localized cases in the Overholt series is 32 per cent, as compared with 26 per cent in the Ochsner group. Adjustment of all three gToups to the stage distribution of the total 518 cases in the study (30 per cent localized and 70 per cent not-localized) yields identical survival rates (21 per cent) for the two treatment groups at the Overholt Clinic. The 5-year survival rate for the Ochsner pneumonectomy group is elevated by 2 points to 17 per cent. 100 90 80 70
- . 60 UI
o o d. 30 _J
I > 3
20
OT H Z W
o
85
,0 Lobectomy (Overholt) - Pneumonectomy (Overholt) ■ Pneumonectomy (Ochsner)
a.
0
_l_
1
2
3
4
5
YEARS AFTER SURGERY Fig. 1.—Cumulative survival curves by stage of disease and operation: surgically treated lung; cancer patients. Ochsner Clinic, 1948-1956 ; Overholt Clinic, 1951-1956.
In Pig. 1, separate survival curves are shown for the localized and the not-localized cases. It is obvious that the survival of patients with localized disease is practically identical in all three operation groups. The 5-year survivals in not-localized cases, however, are significantly lower following the Ochsner pneumonectomy than following the Overholt pneumonectomy. The results in not-localized cases following Overholt lobectomy are not significantly different from either pneumonectomy group; the survival curve is somewhere between the two pneumonectomy groups for the entire 5-year period. Mediastinal Dissection and Adjuvant Treatment.—It has been pointed out already that there were other identifiable differences in the treatment at the Overholt and Ochsner clinics that are not encompassed by the two types of
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operation. Two of these variables are mediastinal lymph node dissection and the use of adjuvant therapy, both of which were more frequently carried out at the Ochsner than at the Overholt clinic. What, then, is the effect of these differences on the end results? The findings with respect to lymph node dissection are summarized in Table III. Among localized cases, the observed survival rates for the various subgroups were not significantly different. Among not-localized cases, the sur vival rate was higher for Overholt patients treated by pneumoneetomy plus hilar node resection than in other subgroups. I t is of interest that the survival of patients in the Overholt Clinic who were treated by pneumoneetomy with resection of mediastinal nodes, the operation which most closely resembles the Ochsner pneumoneetomy, was very similar to the survival of patients at the Ochsner Clinic. This was true for both localized and not-localized cases. TABLE I I I . FIVE-YEAR SURVIVAL R A T E S BY STAGE OF DISEASE, OPERATION, AND E X T E N T OF L Y M P H NODE RESECTION: SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND E X T E N T OF L Y M P H NODE RESECTION
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE NO.
%
(%)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
(%)
5-YEAR SURVIVAL RATE NO.
%
(%)
Localized All cases No nodes Hilar only Mediastinal
60 18 25 17
100 30 42 28
40 53 31 44
45 7 19 19
100 16 42 42
35 38 30 39
49 1 1 47
100 2 2 96
39
Not localized All cases No nodes Hilar only Mediastinal
56 13 19 24
100 23 34 43
12 0 16 17
166 7 56 103
100 4 34 62
15 (0) 25 9
142 3 5 134
100 2 4 94
7
39
(0) 7
All stages 15 191 100 19 211 100 116 100 27 All cases 2 21 31 31 No nodes 4 27 14 7 3 26 24 44 6 75 36 38 Hilar only (») 14 41 95 181 58 35 28 15 122 Mediastinal Note: (1) Percentages may not total 100 because of rounding. (2) Rates based on 5-9 eases shown in parentheses; no rates shown for less than 5 cases.
The clinical significance of the above observations is difficult to evaluate, since the considerations which led to the use of more extensive surgery in some cases and less extensive surgery in others are not fully known. However, the available evidence suggests that less extensive surgical procedures are related to survival rates that are at least as good as, and perhaps better than, those recorded following more extensive surgery. It is necessary to note that the basis for determination of the extent of the tumor is not identical in the groups that are being compared, since such cate gorization is made on the combined clinical and pathologic evidence. A greater amount of lung tissue and usually more lymph nodes are available for examina tion following pneumoneetomy than after lobectomy. A case classified as
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localized following pneumonectomy with mediastinal lymph node dissection would thus be based on more evidence than would be available following the ex amination of tissues by lobectomy with limited or no lymph node dissection. It is thus possible that some cases of treatment by lobectomy and classified as localized would have been categorized as not-localized if more extensive opera tion had been performed. This would tend to understate the survival of patients with localized tumors who were treated by lobectomy. In spite of this possible downward bias, it is noteworthy that the observed survival among cases classified as localized after lobectomy was at least as good as that observed in cases classified as localized on the basis of evidence obtained from pneumonec tomy. TABLE I V . FIVE-YEAR SURVIVAL B A T E S BY STAGE OF D I S E A S E , OPERATION, AND U S E OF ADJUVANT T H E R A P Y ; SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND ADJUVANT THERAPY
Localized All cases Surgery only Surgery plus* Not localised All eases Surgery only Surgery plus*
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE
%
(%)
60 60 0
100 100 0
40 40
56 48 8
100 86 14
12 15 (0)
NO.
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE
%
(%)
45 39 6
100 87 13
35 32 (50)
166 129 37
100 78 22
15 16 12
NO.
5-YEAR SURVIVAL RATE
%
(%)
49 44 5
100 90 10
39 42 (20)
142 80 62
100 56 44
7 8 5
NO.
All Stages All eases 211 100 116 100 27 19 191 100 15 65 29 Surgery only 93 108 168" 80 19 124 20 Surgery plus* 35 20 7 (0) 43 8 67 6 17 Note: Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases. *X-ray and/or chemotherapy.
The frequency with which x-ray therapy and chemotherapy was used in each of the clinics was discussed in the section entitled "General Nature of Data.'' At the Overholt Clinic, x-ray was the predominant adjuvant treatment, whereas nitrogen mustard was the usual adjuvant at the Ochsner Clinic. Table IV summarizes the information on the effect of these adjuvant procedures on survival. From the available data one can only say that, with the specific modalities, doses, and time schedules employed, there is no evidence that these additional measures had a significant influence on survival. It should be emphasized that the choice of mediastinal dissection at the Overholt Clinic, or the choice of ancillary treatment at both clinics for any individual patient, was based on some real or presumed indication and, thus, introduces a factor of selection. The influence of this selection can be estimated to some degree by comparing the results with those from the other clinic, where such selection is practiced to a lesser degree. Nevertheless, all that can be cor-
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rectly concluded is that under the specific conditions, no demonstrable improve ment in survival was achieved by these ancillary procedures. If these procedures were systematically reserved for patients with a graver prognosis, some beneficial effect may have been achieved, albeit not manifest in additional survival. A t best, the effects could have been rather minor, and would require a systematic, designed clinical trial if an explicitly correct conclusion were to be reached. Site of the Primary Tumor.—The distribution of eases with respect to site of the primary tumor within the lung (central, right lung, left lung) was very similar in the two clinics. At the Overholt Clinic, 7 per cent of the tumors were central, 49 per cent were in the right lung, and 44 per cent were in the left lung. TABLE V.
FIVE-YEAR SURVIVAL RATES BY STAGE OF D I S E A S E , OPERATION, AND ORIGIN OF T H E L E S I O N : SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND ORIGIN OF LESION
Localized All oases Central Right lung Upper and middle lobes Lower lobe Left lung Upper lobe Lower lobe Not Localized All cases Central Right lung Upper and middle lobes Lower lobe Left lung Upper lobe Lower lobe
PNEUMONECTOMY OVERHOLT)
(
5-YEAR SURVIVAL RATE
SURVIVAL 5-YEAR RATE
%
(%)
NO.
%
(%)
60* 1 34
100 2 57
40
100 9 42
35
40
45 4 19
22 12 24 17 6
37 20 40 28 10
41 40 41 38 (67)
10 9 22 12 10
56 0 37
100 0 66
12
24 12 19 16 3
43 21 34 29 5
NO.
-
10 8 17 16 12
-
PNEUMONECTOMY OCHSNER) 5-YEAR SURVIVAL RATE
%
(%)
47
49 8 21
100 16 43
39 (25) 57
22 20 49 27 22
50 (43) 23 19 20
14 7 20 14 6
29 14 41 29 12
42 (86) 27 26 (30)
166t 19 68
100 11 41
15 25 10
142 15 73
100 11 51
7 13 8
46 19 77 48 24
28 11 46 29 14
12 7 18 15 17
46 24 54 26 24
32 17 38 18 17
6 12 4 8 0
-
NO.
All Stages 191 100 15 All cases 116* 100 27 19 211t 100 1 23 12 Central 1 23 26 17 11 Right lung 87 18 94 19 71 61 25 41 49 Upper and middle lobes 46 40 24 56 27 31 15 19 60 Lower lobe 24 21 29 28 13 19 31 16 29 Left lung 43 37 30 99 47 19 74 39 10 16 40 21 14 28 60 28 Upper lobe 33 25 Lower lobe 9 8 (56) 34 16 18 30 16 6 Note: (1) The right middle lobe is not shown separately. This site accounted for approximately 5 per cent of the cases in each stage-operation subgroup. Cases of unspecified lobe origin are included in the right and left lung totals. (2) Rates based on 5-9 cases are shown In parentheses; no rates shown for less than 5 cases. •Includes one case of bilateral origin. tlncludes 2 cases of unspecified origin.
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The corresponding percentages at the Ochsner Clinic were 12, 49, and 39. How ever, at the Overholt Clinic, a greater percentage of tumors treated by lobectomy were in the right lung—61 per cent, contrasted with 41 per cent of those treated by pneumonectomy (Table V ) . There is no clear relationship between the location of the tumor and the 5-year survival rates. Adjustment for differences in the distribution of cases with respect to site of origin has virtually no effect on the survival rates for each of the three treatment groups. It is concluded that there is no demonstrable effect of tumor location on the relationship among the three groups. TABLE V I . FIVE-YEAR SURVIVAL R A T E S BY STAGE OF DISEASE, OPERATION, AND SIZE OF LESION : SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT) 5-YEAR SURVIVAL RATE
STAGE AND SIZE OF LESION
NO.
Localized All cases Small Medium Large Unspecified (Average size)
60 100 I s "30 23 38 17 28 2 3 (4.9 cin.)
Not Localized All cases Small Medium Large Unspecified (Average size)
PNEUMONECTOMY (OVERHOLT)
%
(%) 40 45 36 37
-
56 100
12
4 ~T
_
20 26 6
36 0 15 46 11 (0) (6.3 cin.)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
(%)
45 100 35 34 ~I3~" ""29" 12 27 32 19 12 27 8 18 (62) (4.9 cm.) 166 100 23 "14" 65 39 58 35 20 12 (5.7 cm.)
15 4 18 14 18
5-YEAR SURVIVAL RATE
%
(%)
49 100
39 (42) 43 38
NO.
9
21 15 4
U
43 31 8 (5.4 cm.)
142 100
~U TT' 57 56 13
40 39 10 (5.9 cm.)
7 "O 11 5 8
All Stages 15 19 191 100 All cases 27 116 100 211 100 25 "13 15 15 Small ~22" "19 36 ~TT "46 43 37 19 77 36 20 78 41 20 Medium 15 43 37 24 70 33 71 37 12 Large 8 7 28 13 31 17 9 Unspecified (12) 12 (5.6 cm.) (Average size) (5.6 cin.) (5.8 cm.) Note: (1)Percentages may not total 100 because of rounding. (2) Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases.
Size of Primary Tumor.—Measurements of the primary tumors in the resected lungs were examined for the possible effect of tumor size on prognosis, and for differences in the distribution of tumor size in the three operation groups. For purposes of presentation, the tumor measurements were divided into three categories of small (under 3 cm. in the largest diameter), medium (3.0 to 5.9 cm.), and large (6 cm. or over). Table V I summarizes these data. There is, at best, but a suggestion of an inverse relationship between size and survival in the Overholt resections of localized neoplasms, but none of the differences in survival rates are statistically significant, and no consistent relationships are evident in other groups. There was a slightly larger proportion of tumors classified as " s m a l l " in the Overholt
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than in the Ochsner series, but the distributions were not significantly different. Patients with localized disease had somewhat smaller tumors than patients with not-localized disease, but the analysis by stage showed no significant differences among the operation groups with respect to average tumor size. Standardization of the survival rates with respect to tumor size has no significant effect on the relationship among the three operation groups. There fore, there is no demonstrable evidence that the size of the primary tumor, in the range represented in these resections, influenced the survival rates or was an important factor of difference between the three operation groups. TABLE V I I .
FIVE-YEAR SURVIVAL RATES BY STAGE OF DISEASE, OPERATION, TYPE: SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND HISTOLOGIC TYPE
Localized All cases Epidermoid A denoearcinoma Undifferentiated Not Localized All cases Epidermoid Adenoearcinoma Undifferentiated
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE
%
(%)
100 45 42 13
40 50 34 (25)
56 100 ~22~ "39 17 30 17 30
12 l3~ 14 0
NO.
60 27 25 8
AND HISTOLOGIC
PNEUMONECTOMY (OCHSNER) 5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
%
(%)
45 29 6 10
100 64 13 22
35 38 (50) 20
166 85 27 54
100 51 16 33
15 19 12 9
NO.
All Stages 116 100 211 100 All cases 27 19 49 42 114 54 24 Epidermoid 38 42 36 33 Adenoearcinoma 26 16 19 25 64 22 8 Undifferentiated 30 11 Note: (1) Percentages may not total 100 because of rounding-. 5-9 cases shown in parentheses.
%
(%)
49 36 6 7
100 73 12 14
39 41 (50) 14
.142 30 27
100 60 21 19
7 13 0 1
191 121 36 34
100 63 19 18
15 21 8 3
NO.
~8F
(2) Rates based on
Histologic Type.—The tumors were classified into three categories with respect to histologic characteristics: (1) epidermoid or squamous cell carcinoma; (2) adenoearcinoma—this category includes 8 bronchiolar (alveolar) tumors in the Overholt series and 3 in the Ochsner series, and one malignant bronchial adenoma in the Overholt series; and (3) undifferentiated (anaplastic, pleomorphic) carcinoma—this category includes 2 oat cell tumors in the Overholt series and one in the Ochsner series. The findings by histologic type are given in Table VII. Tumors designated by pathologists as epidermoid were relatively more fre quent in the Ochsner series (63 per cent) than in the Overholt series (50 per cent). Tumors classified as undifferentiated were less frequent in the Ochsner series (18 per cent versus 27 per cent in the Overholt series). Survival at 5 years was rather uniformly low among patients with tumors of the undifferen tiated type in each treatment group. In this respect, the material is somewhat weighted against the Overholt series. Among both localized and not-localized
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cases there were relatively more adenocarcinomas in the lobectomy group than in the two pneumonectomy groups. In spite of the differences in the histologic distribution of cases within treatment groups, standardization of survival rates with respect to histology has little effect on the relationship among the three groups. Among localized cases, the histology-standardized rates were 42 per cent for the Overholt lobec tomy, 38 per cent for the Overholt pneumonectomy, and 39 per cent for the Ochsner pneumonectomy. The corresponding adjusted survival rates for notlocalized cases were 15, 15, and 7 per cent. TABLE V I I I .
STAGE AND AGE A T DIAGNOSIS
Localized All cases <50yr. 50-59 yr. 60-69 yr. 70+ yr. (Average age) Local ized All cases < 5 0 yr. 50-59 yr. 60-69 yr. 70+yr. (Average age)
FIVE-YEAR SURVIVAL BATES BY STAGE OF DISEASE, OPERATION, SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956
AGE:
LOBECTOMY (OVERHOLT)
P N E U MONECTOM Y (OVERHOLT)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL SATE
(%)
(%)
(%)
NO.
%
60 12 15 25 8
100 20 25 42 13
OB RELA SERVED TIVE*
40 46 56 33 (30)
47 47 61 40 (46)
NO.
%
45 5 15 23 2
100 11 33 51 4
^(60 years)
OB RELA SERVED TIVE*
35 40 43 31
39 41 47 38
-
-
NO.
49 12 18 14 5
(60 y ears)
% 100 24 37 29 10
OB RELA SERVED TIVE*
39 25 52 41 (20)
45 26 57 50 (30)
(57 years)
Not
56 9 18 19 10
100 16 32 34 18
12 11 17 12 0
(60 pears)
13 11 18 15 0
166 27 72 59 8
100 16 43 36 5
15 19 14 16 12
(58 years)
18 20 15 20 18
142 31 59 47 5
100 22 42 33 4
7 7 10 5 (0)
8 7 11 6 (0)
(57 years)
All Stages 19 All cases 116 100 27 31 211 100 23 191 100 15 17 32 12 12 22 15 23 43 23 21 33 34 < 5 0 yr. 18 50-59 yr. 87 41 19 21 77 33 28 35 38 40 20 22 60-69 yr. 44 38 24 29 82 39 20 25 61 32 13 16 70+ yr. 10 10 10 18 16 13 20 5 15 5 10 15 (Average age) (60 : (rears) (58 y ears) (57 years) Note: (1) Percentages may not total 100 because of rounding. (2) Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases. •Relative survival rates are obtained by adjusting the observed rates for normal life expectancy.
Effect of Age and Sex.—Table V I I I summarizes the effect of age on sur vival, by the relevant operation groups and extent of disease. The 327 patients in the Overholt series were somewhat older, with a mean age of 59 years; the mean age of 191 Ochsner patients was 57 years. The slight under-representation of older patients in the Ochsner group is in part due to the exclusion of 13 patients who were considered ineligible for pneumonectomy and on whom lobectomy was performed; their average age was 63 years. There is no consistent or significant effect of age on survival, particularly
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when the figures are adjusted for the expected mortality in each group and the relative survival figures derived. Upon age-adjusting the observed or relative rates, it is concluded that the age differences among various operation groups and the two clinics are not an important variable influencing survival. TABLE I X .
FIVE-YEAR SURVIVAL KATES BY STAGE OP DISEASE, OPERATION, AND S E X : SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE STAGE AND S E X
Localized All cases Male Female Not Localized All cases Male Female
(%)
NO.
%
(%)
60 100 49 82 11 18
40 41 40
43 2
96 4
35
56
12
166
100
16 0
151 15
91 9
15 15 7
44 12
100 79 21
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
%
NO.
PNEUMONECTOMY (OCHSNER)
%
(%)
43 6
88 12
39 (33)
142
100
124 18
87 13
7 8 0
NO.
All Stages All cases 116 100 211 100 19 27 191 100 15 93 194 92 Male 80 29 20 87 16 167 Female 12 13 23 19 17 24 20 8 8 Note: Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases.
The proportion of females in the Overholt and Ochsner series is almost identical—approximately 12.5 per cent in each. However, relatively more women were treated by lobectomy than by pneumoneetomy at the Overholt Clinic (Table I X ) . Among localized cases, survival among male and female patients was similar, but female rates were lower among not-localized cases. The number of female patients in this study is too small for a meaningful comparison with the survival experience of male patients. On a wider national basis, the survival of females was found to be better than of males, particularly among surgicallytreated localized cases.8 Sex adjustment of the survival rates for the three treatment groups left the rates virtually unchanged. I t is, therefore, concluded that sex differentials are not of sufficient importance to alter any prior conclusions. DISCUSSION
The data available from the Overholt and the Ochsner clinics on the treat ment and survival of patients with bronchogenic carcinoma were compared with similar data obtained from 99 hospitals in the United States, on over 8,800 cases, as reported by the End Results Group of the National Cancer Institute. 9 The end results are similar and emphasize the universally grim prognosis of this neoplastic disease. The broad experience of the 99 hospitals from 1950 to 1957 was as follows:
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8,807 confirmed diagnoses of bronchogenic carcinoma were made; 29 per cent of these patients were surgically treated; 5-year survival in cases of resection was approximately 16 per cent, and among all patients was 6 per cent. From the findings of this and previously reported studies, 1 ' 6 resectability rates pertaining to the same period of time at the Overholt and Ochsner clinics were approximately 40 per cent; 5-year survival in all cases of resection was approximately 20 per cent; this represents a 5-year survival of about 8 per cent among all patients with bronchogenic carcinoma seen at these two clinics. This small salvage is achieved only by surgical resection. The point of this report is to analyze whether the type of surgical resection significantly affects the results. The available data lead to these conclusions: 1. Survival after surgical resection was primarily determined on whether the tumor was found to be localized or had extended to lymph nodes or con tiguous tissues beyond the lung. 2. Survival in patients with localized lung cancer was similar whether lobectomy or pneumonectomy was performed. The available evidence does not clearly delineate the efficacy of lymph node dissection. 3. Survival of patients with not-localized carcinomas was lower following pneumonectomy with mediastinal lymph node dissection than after more limited pneumonectomy or lobectomy. 4. Survival in these series was not demonstrably improved by the addition of x-ray therapy or chemotherapy with an alkylating agent. 5. Tumors classified as being histologically undifferentiated had a graver prognosis than the epidermoid neoplasms or the adenocarcinomas. 6. Survival was not demonstrably related to the size of the primary tumor, the site of the primary tumor within the lung, or the age and sex of the patient. It is difficult to accept the third conclusion, that a more limited surgical removal of a not-localized neoplasm produces more actual salvage than the more extended resection. The interpretation perforce is that the latter pro cedure not only has a higher immediate postoperative mortality but an in creased mortality over the whole 5-year postoperative course. More briefly and directly: the less extensive operations do not save more patients, but the more extensive operations increase mortality. It is essential to point out that no extrapolations beyond the data and their limitations are possible. An attempt was made to measure the effect of such factors as histologic type, size and location of the lesion, and the age and sex of the patients on the survival rates for the three treatment groups. Treating each factor independently, no significant effect was demonstrated. However, this does not mean that some combination of factors may not affect survival. The series at hand is too small to permit this type of an analysis. Furthermore, although the evidence suggests that lobectomy with regional lymph node removal is an adequate operation for patients with neoplasms surgically circumscribable by this procedure, it does not follow that even more limited operations may be desirable. On the other hand, such procedures in combination with, say, preoperative x-ray therapy, may be worth considering for controlled clinical trials.
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The tragic limitations of effective treatment of bronchogenic carcinoma, and the established causation of an important proportion of this neoplasm bycigarette smoking, make the disease a challenge to preventive medicine as well as to cancer research. SUMMARY
The survival experience of lung cancer patients treated surgically at the Ochsner and Overholt clinics has been analyzed in order to evaluate the relative merits of lobectomy and pneumonectomy. Available for the main analysis were 116 Overholt lobectomies, 211 Overholt pneumoneetomies, and 191 Ochsner pneumonectomies. Among the localized cases, the 5-year survival rates for the above-mentioned groups were not significantly different, being 40, 35, and 39 per cent, respectively. Analyses carried out on the possible affect of various factors which might in fluence survival revealed differences of such degree and direction so as not to alter this conclusion. Among not-localized cases, the 5-year survival rates for the three groups were 15, 12, and 7 per cent, respectively. The significant difference in survival between the Overholt and Ochsner pneumonectomy groups was mainly asso ciated with extent of lymph node dissection. Among those Overholt and Ochsner patients treated by pneumonectomy with mediastinal lymph node dissection, the operation usually performed at the Ochsner Clinic, the survival rates were very similar, 9 and 7 per cent, respectively. However, at the Overholt Clinic, a group of 56 patients undergoing pneumonectomy with dissection of only the hilar nodes had a survival rate of 25 per cent. The clinical significance of the above differences were difficult to evaluate since the considerations which led to the use of more extensive surgery in some cases and less extensive surgery in others were not fully known. However, the available evidence suggests that less extensive surgical procedures were related to survival rates that were at least as good as, and perhaps better than, those recorded following more extensive surgery. REFERENCES
1. Overholt, R. H., and Bougas, J . A . :
Common Factors in Lung Cancer Survivors, J .
THORACIC SURG. 32: 508-517, 1956.
2. Lawrence, G. H., Walker, J . H., and Pinkers, L . : Extended Resection of Bronchogenic Carcinoma: A Reappraisal and Suggested Plan of Management, New England J . Med. 263: 615-620, 1960. 3. Jones, J . C , Robinson, J . L., Meyer, B . W., and Motley, H . L . : Primary Carcinoma of the Lung. A Follow-up Study Involving Pulmonary Function Studies of Long-Term Survivors, J . THORACIC SURG. 39: 144-158, 1960.
4. Overholt, R. H . : The Surgical Treatment of Bronchogenic Cancer, Proc. Fourth National Cancer Conference, Philadelphia, 1960, J . B . Lippincott Co., p p . 309-314. 5. Ochsner, A., Ray, C. J., and Acree, P . W . : Cancer of the Lung, Am. Rev. Tuberc. 70: 263-259, 1954. 6. Ochsner, A., Ochsner, A., J r . , H 'Doubler, C , and Blalock, J . : Bronchogenic Carcinoma, Dis. Chest 3 7 : 1-12, 1960. 7. Cutler, S. J., and Ederer, F . : Maximum Utilization of the Life Table Method in Analyzing Survival, J . Chron. Dis. 8: 699-712, 1958. 8. Mersheimer, W. L., and Ederer, F . : E n d Results Evaluation of Cancer of the Lung and the Bronchus, Proc. Fourth National Cancer Conference, Philadelphia, 1960, J . B. Lippincott Co., p p . 319-322. 9. End Results and Mortality Trends in Cancer, National Cancer Institute Monograph No. 6, Washington, D. C , TJ. S. Gov't Printing Office, 1961.
LOBECTOMY
I N BRONCHOGENIC CARCINOMA A Comparison of End Results of the Overholt and Ochsner Clinics M. B. Shimkin, M.D., R. R. Connelly, B.S., S. C. Marcus; B.S.,* and S. J. Cutler, Sc.D., Bethesda,
Md.
T
HERE is general agreement that surgical resection is the only curative thera peutic modality in bronchogenic cancer. There is no general agreement, however, regarding the type of resection that should be carried out. Some thoracic surgeons recommend the radical pneumonectomy with en bloc mediastinal lymph node dissection, whereas other centers carry out more limited pro cedures, such as lobectomy, with such mediastinal lymph node dissection as the exposure allows. A typical exchange of views on this subject followed the presentation of the paper by Overholt and Bougas 1 in 1956. These differences of opinion among surgeons remain unresolved. A summary of 10 large series encompassing 7,868 patients with bronchogenic carcinoma2 demonstrated the following features: (1) of those in whom diagnosis is made, just over 50 per cent undergo thoracotomy; (2) in those who have exploratory operations, approximately 60 per cent of the lesions are found to be resectable; and (3) the 5-year survival in all cases is under 10 per cent, and approximately 20 per cent in patients with resectable lesions. There are no publications on acceptably comparable groups of patients treated by pneumonec tomy and by lobectomy to indicate the relative merits of the two types of opera tion. However, there is evidence that postoperative mortality and morbidity are higher among patients subjected to the more extensive resection. 2 ' 3 Definitive comparison between pneumonectomy and lobectomy for bron chogenic carcinoma requires carefully planned and executed clinical trials that would include random assignment of patients to the treatment groups being compared. In the absence of data from such trials, sources of information for comparing the results of lobectomy and pneumonectomy are limited to selected surgical centers with different policies of treatment. At the second workshop on lung cancer research sponsored by the American Cancer Society and held at Arden House on February 27 to March 1, 1959, it was suggested that a more systematic analytical comparison of available data
D. C.
From the National Cancer Institute, Bethesda, Md. Received for publication Jan. 2, 1962. ♦Present address: Division of Air Pollution, U. S. Public H.-alth Service, Washington, 503
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would be desirable. As a result, Dr. Alton Ochsner of New Orleans, who has consistently espoused pneumonectomy for lung cancer, and Dr. Richard H. Overholt of Boston, who during more recent years has tended to use lobectomy as the treatment of choice, agreed to permit the Biometry Branch of the National Cancer Institute to compare the survival of their surgically treated patients. A protocol followed in abstracting information on patients with lung cancer, developed by the End Results Group of the National Cancer Institute, was modified for this purpose. We are greatly indebted to Dr. Ochsner and to Dr. Overholt for their full cooperation in making all necessary records available for abstracting. The analyses and interpretations of their data are the responsibility of the authors, and were prepared independently of the surgeons involved. The manuscript in its completed form, of course, was seen by Drs. Ochsner and Overholt, who corrected errors of fact and expressed their opinions of the analysis. The report is thus published with their knowledge. Such knowledge does not necessarily imply either approval or agreement by either or both surgeons. GENERAL N A T U R E OF DATA
Overholt Data.— At the Overholt Thoracic Clinic, there has been a shift in policy from pneumonectomy to lobectomy as the treatment of choice for bronchogenic cancer. During the period selected for study, 1951-1956, the proportion of lobectomies among the resections increased from 20 per cent in 1951 to 45 per cent during 1955-1956. Dr. Overholt described current practice as follows,4 " O n explora tion, the uppermost lymph node is removed from the mediastinum and examined histologically; all visible lymph nodes are resected whether one is doing a lobectomy or a pneumonectomy. . . . The extent of research depends on the extent of the tumor. . . . I see no reason to take out an entire lung when a person has a very small localized cancer in one lobe, particularly where lymph nodes are negative." During the period of shift toward preservation of pulmonary tissue, a more aggressive approach has been evident toward the management of the lymph nodes. During 1951-1954, mediastinal lymph nodes were resected in 40 per cent of the "pneumonectomies" and in 18 per cent of the "lobectomies." During 1955-1956, mediastinal lymph node resection was carried out in 94 per cent of the "pneumonectomies" and in 56 per cent of the "lobectomies." The over-all experience at the Overholt Clinic was summarized by Overholt and Bougas in 1956.1 During the period 1941-1955, 1,237 patients with pri mary lung cancer were seen. Of these, 64 per cent .were explored and in 65 per cent of those explored, or in 42 per cent of the total, resections were per formed. The study group from the Overholt Clinic consisted of the 331 surgicallytreated patients with primary carcinoma of the lung, diagnosed during the years 1951-1956, inclusive. Four of these cases were excluded from this study. Two patients were operated upon elsewhere by surgeons not on the Overholt
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staff. Another patient, diagnosed elsewhere and considered inoperable, did not undergo operation until 9 months after diagnosis. The fourth case was excluded because the resected tumor later proved to be a metastasis from carcinoma of the bladder. Thus, 327 patients surgically treated by Dr. Diehard Overholt or members of his staff were included in this analysis. Of these, 211 were classified as "pneumonectomies" and 116 as "lobectomies." However, the Overholt "pneumonectomy" group includes 89 patients in whom systematic mediastinal lymph node resection was not carried out. Under the designation of "lobectomy," 75 patients did not have a mediastinal lymph node resection. This group also includes 14 patients in whom two lobes of the right lung were removed, and 4 patients in whom the operation was limited to a segmental resection. In one patient, lobectomy was followed by a segmental resection on the opposite side 2 weeks later for a bilateral lesion. At the Overholt Clinic, the primary treatment for lung cancer was limited to surgery in 80 per cent of the "pneumonectomies" and in 93 per cent of the "lobectomies." X-ray treatment was employed in 41 cases of pneumonectomy (19 per cent) and in 7 cases of lobectomy (6 per cent). Only 2 patients re ceived adjuvant chemotherapy (nitrogen mustard) following pneumonectomy as part of their primary treatment, and one patient received both x-ray and chemotherapy following lobectomy. Ochsner Data.— The following statement by Dr. Ochsner reflects the surgical procedure that is followed at the Ochsner Clinic.5 "Although it has been advocated by some that lobectomy may be used in the treatment of bronchogenic cancer and although certain patients with cancer of the bronchus can be cured by lobectomy, we are convinced that lobectomy is not a good cancer operation and should not be used except in the patient in whom careful preoperative pulmonary function studies indicate that the patient cannot tolerate a pneumonectomy." This policy is reflected in the fact that over 90 per cent of resections for lung cancer were pneumonectomies during the period selected for study, 1948-1956, and lobectomy was reserved for patients who were considered unable to tolerate more extensive surgical procedure. In 1960, Ochsner and his associates6 summarized the total experience at the Ochsner Clinic and Foundation Hospital from 1942 to 1957 as follows: There were 875 cases of primary lung cancer, in which 525 of the patients were explored (60 per cent). Kesection was performed in 356 patients, who con stituted 68 per cent of the cases of exploration, or 41 per cent of the total cases. The study group from the Ochsner Clinic consisted of the 205 patients who were subjected to resection during the period 1948-1956, inclusive. The 3 earlier years, 1948-1950, not represented in the Overholt series, were included in order to increase the pneumonectomy series to approximately the same number as in the Overholt group. Deletion of these cases would not alter or modify significantly any of the findings. One case was excluded from this analysis; this patient had had a lobectomy elsewhere and the resection was extended at the Ochsner Clinic several months later.
TABLE I .
LOBECTOMY MONTHS AFTER OPERA TION 0.0- 0.9 1.0- 1.9 2.0- 2.9 3.0- 3.9 4.0- 4.9 5.0- 5.9 6.0- 8.9 9.0-11.9 12.0-17.9 18.0-23.9 24.0-29.9 30.0-35.9 36.0-41.9 42.0-47.9 48.0-53.9 54.0-59.9 60.0 +
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ALIVE AT BEGINNING OF INTERVAL 116 103 98 96 93 87 83 75 65 54 44 42 36 34 26 20 14
DIED DURING INTERVAL 13 5 2 3 6 4 8 10 11 10 2 2 1 2 1 2
DETAILED L I F E TABLE ANALYSIS BY OPERATION: OCHSNER CLINIC, 1948-1956;
(OVERHOLT) ALIVE AT LAST CONTACT* WITH DRAWN LOST
_ -
-
2
2 1 5 5 4
1
-
PNEUMONECTOMY PERCENT ALIVE AT END OF INTERVAL 89 84 83 80 75 72 65 56 47 38 36 34 33 31 30 27
ALIVE AT BEGINNING OF INTERVAL 211 183 165 154 150 142 131 110 95 75 64 51 44 37 33 28 27
DIED DURING INTERVAL 26 16 11 4 8 11 21 15 19 11 12 4 3 1 3
-
*If date of last contact was earlier than 1959, classified as "lost" to follow-up; if 1959 or
Only 13 of the 204 Ochsner patients were treated by lobectomy, one by a segmental resection and one by right bilobectomy. Pulmonary or cardiac function studies indicated that only a lobectomy could be tolerated by 10 of these patients. In 3 other patients a pneumonectomy seemed contraindicated because of invasion of tumor beyond the thorax. Four patients at the Ochsner Clinic underwent a lobectomy which was followed in 4 to 21 days by complete removal of the remaining lung tissue on the same side. These patients were classified as "pneumonectomies." The term "pneumonectomy" at the Ochsner Clinic covers an operation performed somewhat differently from that at the Overholt Clinic. At the Ochsner Clinic, where pneumonectomy is the treatment of choice, the standard procedure is the removal of the entire involved lung with an en bloc excision of the mediastinal nodes. This policy is reflected in the present series. In only 10 of the 191 Ochsner "pneumonectomies" were the mediastinal nodes not removed. At the Ochsner Clinic, 65 per cent of the patients who underwent a pneu monectomy received no adjuvant therapy. In 35 per cent, the primary treat ment included the addition of x-ray therapy (3 per cent), chemotherapy with nitrogen mustard 27 per cent), or both (5 per cent). The injections of nitrogen mustard were often repeated during the subsequent course of treatment. Total Data.— For the main analysis, therefore, there were available three main groups of patients treated surgically for primary lung cancer: (1) Overholt "pneu monectomies," 211 patients; of these, 122 (58 per cent) had mediastinal lymph node dissection as part of the operation; (2) Overholt "lobectomies," 116 pa tients; of these, 41 (35 per cent) had mediastinal lymph node resection as the
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SURGICALLY TREATED L U N G CANCER PATIENTS OVERHOLT CLINIC, 1951-1956 (OVERHOLT) ALIVE AT LAST CONTACT* WITH LOST DRAWN
-
1 3 2 3 2 1
■
PERCENT ALIVE AT END OF INTERVAL 88 80 75 73 69 63 53 46 37 31 25 23 22 21 19 19
ALIVE A T BEGINNING OF INTERVAL 191 156 145 133 128 114 102 86 76 52 44 38 38 33 29 26 21
PNEUMONECTOMY (OCHSNER) ALIVE AT LAST CONTACT* WITH DIED DURING LOST DRAWN INTERVAL 35 11 12 5 14 12 16 10 24 8 6 0 4 1 1 2
_ _ _ _ 1 3 2 3
PERCENT ALIVE AT END OF INTERVAL 82 76 70 67 60 53 45 40 27 23 20 20 18 17 17 15
later, classified as "withdrawn" alive.
exposure allowed; and (3) Ochsner "pneumonectomies," 191 patients; of these, 181 (95 per cent) had mediastinal lymph node dissection, usually en bloc with the lung. The 13 Ochsner " lobectomies" occurred in a selected group of patients, as previously mentioned. There were no postoperative deaths in the 13 cases and 6 survived the first year, but there were no 5-year survivors. This group was considered too small for more definitive analysis, and was excluded in the sub sequent presentation. Inclusion of these cases in the Ochsner series would not affect any of the conclusions and interpretations. STATISTICAL ANALYSES
The observed survival rates reported in this study were computed using the actuarial or life-table method as described by Cutler and Ederer. 7 While only the 5-year rates are presented in the subsequent analyses, they were obtained from life-table analyses as detailed as those shown in Table I. All rates were computed using the length of survival from first definitive surgery to the date of last contact. Follow-up information at both clinics was excellent. Only 10 of 327 pa tients were classified as lost to follow-up at the Overholt Clinic, and there were no losses to follow-up among the 204 Ochsner cases. A lost case was defined as any patient alive at last contact but not followed at least into calendar year 1959. Patients lost to follow-up were not excluded from the study. Rather, they were entered in the life-table analysis as patients under observation from the date of surgery to the date last known to be alive. In effect this means that subsequent to the date of last contact, lost patients were assumed to have
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experienced a survival pattern similar to the patients who remained under follow-up study. Only observed cumulative survival rates are presented in this paper. Ex tending the analysis to include relative survival rates, which adjust the observed survival rates for normal life expectancy, was considered. Using appropriate Massachusetts and Louisiana State life tables, the 5-year expected survival rates corresponding to the age and sex distributions among lobectomy and pneumonectomy groups at the Overholt Clinic and the pneumonectomy group at the Ochsner Clinic were 85, 87, and 88 per cent, respectively. In view of the small differences among the expected survival rates, relationships among the three treatment groups, based on observed survival rates, are almost identical with those based on relative rates. It was, therefore, decided to restrict the presentation to the observed rates, except in the analysis of the association of age and survival. All conclusions in which significant differences between groups are claimed meet appropriate statistical criteria. The level of significance used in all the tests mentioned below was P = 0.05. Thus, an observed difference was ac cepted as statistically significant, if the probability that a difference at least as large as would occur by chance alone was 5 per cent or less. The " t " test was used in testing differences between average ages and average size of lesion, and for testing differences between survival rates. The standard error of a survival rate was computed according to the formula developed by Greenwood. The X2 test for independence was used in comparing the distribution of cases with respect to histologic type, size and location of lesion, and age. RESULTS
The survival experience of the three surgically-treated groups is presented, in the form of a detailed life table, in Table I. The 5-year survival rate was definitely higher for patients treated by the Overholt lobectomy (27 per cent) than for patients treated by pneumonectomy (19 per cent at the Overholt Clinic and 15 per cent at the Ochsner Clinic). All deaths within the first 30 days following operation were classified as operative deaths. At the Overholt Clinic, postoperative mortality was 11 per cent in the lobectomy group and 12 per cent in the pneumonectomy group. Among patients treated by the Ochsner pneumonectomy, postoperative mortality was 18 per cent. Exclusion of postoperative deaths has no significant effect on the relationship of the survival rates for the three operation groups. For ex ample, excluding postoperative deaths, the 5-year survival rates were 30 per cent for the Overholt lobectomy group, 22 per cent for the Overholt pneumonec tomy group, and 19 per cent for the Ochsner pneumonectomy group. These rates compare with rates of 27, 19, and 15 per cent based on all cases of resec tion. All survival rates presented in the discussion that follows include the effect of postoperative mortality. As in all comparisons of results of different procedures and different clinics, the conclusions are valid only to the degree that appropriate considera-
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tion can be made for the various factors of selection that were involved. The question of comparability can be answered only partially in any study not specifically designed to avoid conscious or unintended selection. Nevertheless, it is useful to consider some known factors in order to reveal differences due to selection that can be adjusted for their effects on survival, and to indicate the similarities, and differences among the patients and their disease in the groups that are being compared. The following variables were therefore analyzed: in respect to the neoplasmits extent, its size, location in the lung, and its histologic type; in respect to other treatment-the effect of mediastinal lymph node dissection and of adjuvant x-ray or nitrogen mustard therapy; in respect to the patient-the effect of age and of sex. ANALYSIS OF VARIABLES
Extent of Disease.—The anatomical extent of involvement by a neoplasm is probably the single most important determinant of prognosis. The end results thus inevitably reflect the proportion of patients that enter a series at the localized and more advanced stages of the disease. The three groups of patients under analysis were classified into two stage categories. The "localized" cases were those in which the tumor was confined to the lung or bronchus, and in which the pathologist found no direct extension to neighboring tissues or metastasis to the resected lymph nodes. The "not-localized" cases were those in which there were regional lymph node metastases or extension of the tumor beyond the lung. Also included in this categogory were some patients with evidence of distant spread or distant metastases who nevertheless had pulmonary resections. TABLE I I .
FIVE-YEAR SURVIVAL RATES BY STAGE OF D I S E A S E AND OPERATION: SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY
( OVERHOLT)
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE STAGE o r
DISEASE
Localized Not localized Regional Distant Total, all stages
NO.
%
60 52 56 48 (48) (41) (7) (8) 116 100
(%) 40 12 (14) (0) 27
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
45 21 166 79 (143) (68) (23) (11) 211 100
(%) 35 15 (16) (0) 19
5-YEAR SURVIVAL RATE NO.
%
49 26 142 74 (138) (72) (4) (2) 191 100
(%) 39 7 (7) (0) 15
In Table II, the patients in each of the three treatment groups are classified according to extent of disease, and the 5-year survival rate for each subgroup is given. I t is immediately apparent that the proportion of the more favorable, localized cases is highest in the Overholt lobectomy group, 52 per cent, in con trast with 21 and 26 per cent in the Overholt pneumonectomy and the Ochsner pneumonectomy groups, respectively. It is thus evident that a major factor in the better survival following lobectomy, as seen in Table I, is the greater pro-
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portion of patients with localized tumors that were selected for lobectomy. If the data for both Overholt groups are combined, the proportion of localized cases in the Overholt series is 32 per cent, as compared with 26 per cent in the Ochsner group. Adjustment of all three gToups to the stage distribution of the total 518 cases in the study (30 per cent localized and 70 per cent not-localized) yields identical survival rates (21 per cent) for the two treatment groups at the Overholt Clinic. The 5-year survival rate for the Ochsner pneumonectomy group is elevated by 2 points to 17 per cent. 100 90 80 70
- . 60 UI
o o d. 30 _J
I > 3
20
OT H Z W
o
85
,0 Lobectomy (Overholt) - Pneumonectomy (Overholt) ■ Pneumonectomy (Ochsner)
a.
0
_l_
1
2
3
4
5
YEARS AFTER SURGERY Fig. 1.—Cumulative survival curves by stage of disease and operation: surgically treated lung; cancer patients. Ochsner Clinic, 1948-1956 ; Overholt Clinic, 1951-1956.
In Pig. 1, separate survival curves are shown for the localized and the not-localized cases. It is obvious that the survival of patients with localized disease is practically identical in all three operation groups. The 5-year survivals in not-localized cases, however, are significantly lower following the Ochsner pneumonectomy than following the Overholt pneumonectomy. The results in not-localized cases following Overholt lobectomy are not significantly different from either pneumonectomy group; the survival curve is somewhere between the two pneumonectomy groups for the entire 5-year period. Mediastinal Dissection and Adjuvant Treatment.—It has been pointed out already that there were other identifiable differences in the treatment at the Overholt and Ochsner clinics that are not encompassed by the two types of
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operation. Two of these variables are mediastinal lymph node dissection and the use of adjuvant therapy, both of which were more frequently carried out at the Ochsner than at the Overholt clinic. What, then, is the effect of these differences on the end results? The findings with respect to lymph node dissection are summarized in Table III. Among localized cases, the observed survival rates for the various subgroups were not significantly different. Among not-localized cases, the sur vival rate was higher for Overholt patients treated by pneumoneetomy plus hilar node resection than in other subgroups. I t is of interest that the survival of patients in the Overholt Clinic who were treated by pneumoneetomy with resection of mediastinal nodes, the operation which most closely resembles the Ochsner pneumoneetomy, was very similar to the survival of patients at the Ochsner Clinic. This was true for both localized and not-localized cases. TABLE I I I . FIVE-YEAR SURVIVAL R A T E S BY STAGE OF DISEASE, OPERATION, AND E X T E N T OF L Y M P H NODE RESECTION: SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND E X T E N T OF L Y M P H NODE RESECTION
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE NO.
%
(%)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
(%)
5-YEAR SURVIVAL RATE NO.
%
(%)
Localized All cases No nodes Hilar only Mediastinal
60 18 25 17
100 30 42 28
40 53 31 44
45 7 19 19
100 16 42 42
35 38 30 39
49 1 1 47
100 2 2 96
39
Not localized All cases No nodes Hilar only Mediastinal
56 13 19 24
100 23 34 43
12 0 16 17
166 7 56 103
100 4 34 62
15 (0) 25 9
142 3 5 134
100 2 4 94
7
39
(0) 7
All stages 15 191 100 19 211 100 116 100 27 All cases 2 21 31 31 No nodes 4 27 14 7 3 26 24 44 6 75 36 38 Hilar only (») 14 41 95 181 58 35 28 15 122 Mediastinal Note: (1) Percentages may not total 100 because of rounding. (2) Rates based on 5-9 eases shown in parentheses; no rates shown for less than 5 cases.
The clinical significance of the above observations is difficult to evaluate, since the considerations which led to the use of more extensive surgery in some cases and less extensive surgery in others are not fully known. However, the available evidence suggests that less extensive surgical procedures are related to survival rates that are at least as good as, and perhaps better than, those recorded following more extensive surgery. It is necessary to note that the basis for determination of the extent of the tumor is not identical in the groups that are being compared, since such cate gorization is made on the combined clinical and pathologic evidence. A greater amount of lung tissue and usually more lymph nodes are available for examina tion following pneumoneetomy than after lobectomy. A case classified as
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J. Thoracic and Cardiovas. Surg.
localized following pneumonectomy with mediastinal lymph node dissection would thus be based on more evidence than would be available following the ex amination of tissues by lobectomy with limited or no lymph node dissection. It is thus possible that some cases of treatment by lobectomy and classified as localized would have been categorized as not-localized if more extensive opera tion had been performed. This would tend to understate the survival of patients with localized tumors who were treated by lobectomy. In spite of this possible downward bias, it is noteworthy that the observed survival among cases classified as localized after lobectomy was at least as good as that observed in cases classified as localized on the basis of evidence obtained from pneumonec tomy. TABLE I V . FIVE-YEAR SURVIVAL B A T E S BY STAGE OF D I S E A S E , OPERATION, AND U S E OF ADJUVANT T H E R A P Y ; SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND ADJUVANT THERAPY
Localized All cases Surgery only Surgery plus* Not localised All eases Surgery only Surgery plus*
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE
%
(%)
60 60 0
100 100 0
40 40
56 48 8
100 86 14
12 15 (0)
NO.
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE
%
(%)
45 39 6
100 87 13
35 32 (50)
166 129 37
100 78 22
15 16 12
NO.
5-YEAR SURVIVAL RATE
%
(%)
49 44 5
100 90 10
39 42 (20)
142 80 62
100 56 44
7 8 5
NO.
All Stages All eases 211 100 116 100 27 19 191 100 15 65 29 Surgery only 93 108 168" 80 19 124 20 Surgery plus* 35 20 7 (0) 43 8 67 6 17 Note: Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases. *X-ray and/or chemotherapy.
The frequency with which x-ray therapy and chemotherapy was used in each of the clinics was discussed in the section entitled "General Nature of Data.'' At the Overholt Clinic, x-ray was the predominant adjuvant treatment, whereas nitrogen mustard was the usual adjuvant at the Ochsner Clinic. Table IV summarizes the information on the effect of these adjuvant procedures on survival. From the available data one can only say that, with the specific modalities, doses, and time schedules employed, there is no evidence that these additional measures had a significant influence on survival. It should be emphasized that the choice of mediastinal dissection at the Overholt Clinic, or the choice of ancillary treatment at both clinics for any individual patient, was based on some real or presumed indication and, thus, introduces a factor of selection. The influence of this selection can be estimated to some degree by comparing the results with those from the other clinic, where such selection is practiced to a lesser degree. Nevertheless, all that can be cor-
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rectly concluded is that under the specific conditions, no demonstrable improve ment in survival was achieved by these ancillary procedures. If these procedures were systematically reserved for patients with a graver prognosis, some beneficial effect may have been achieved, albeit not manifest in additional survival. A t best, the effects could have been rather minor, and would require a systematic, designed clinical trial if an explicitly correct conclusion were to be reached. Site of the Primary Tumor.—The distribution of eases with respect to site of the primary tumor within the lung (central, right lung, left lung) was very similar in the two clinics. At the Overholt Clinic, 7 per cent of the tumors were central, 49 per cent were in the right lung, and 44 per cent were in the left lung. TABLE V.
FIVE-YEAR SURVIVAL RATES BY STAGE OF D I S E A S E , OPERATION, AND ORIGIN OF T H E L E S I O N : SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND ORIGIN OF LESION
Localized All oases Central Right lung Upper and middle lobes Lower lobe Left lung Upper lobe Lower lobe Not Localized All cases Central Right lung Upper and middle lobes Lower lobe Left lung Upper lobe Lower lobe
PNEUMONECTOMY OVERHOLT)
(
5-YEAR SURVIVAL RATE
SURVIVAL 5-YEAR RATE
%
(%)
NO.
%
(%)
60* 1 34
100 2 57
40
100 9 42
35
40
45 4 19
22 12 24 17 6
37 20 40 28 10
41 40 41 38 (67)
10 9 22 12 10
56 0 37
100 0 66
12
24 12 19 16 3
43 21 34 29 5
NO.
-
10 8 17 16 12
-
PNEUMONECTOMY OCHSNER) 5-YEAR SURVIVAL RATE
%
(%)
47
49 8 21
100 16 43
39 (25) 57
22 20 49 27 22
50 (43) 23 19 20
14 7 20 14 6
29 14 41 29 12
42 (86) 27 26 (30)
166t 19 68
100 11 41
15 25 10
142 15 73
100 11 51
7 13 8
46 19 77 48 24
28 11 46 29 14
12 7 18 15 17
46 24 54 26 24
32 17 38 18 17
6 12 4 8 0
-
NO.
All Stages 191 100 15 All cases 116* 100 27 19 211t 100 1 23 12 Central 1 23 26 17 11 Right lung 87 18 94 19 71 61 25 41 49 Upper and middle lobes 46 40 24 56 27 31 15 19 60 Lower lobe 24 21 29 28 13 19 31 16 29 Left lung 43 37 30 99 47 19 74 39 10 16 40 21 14 28 60 28 Upper lobe 33 25 Lower lobe 9 8 (56) 34 16 18 30 16 6 Note: (1) The right middle lobe is not shown separately. This site accounted for approximately 5 per cent of the cases in each stage-operation subgroup. Cases of unspecified lobe origin are included in the right and left lung totals. (2) Rates based on 5-9 cases are shown In parentheses; no rates shown for less than 5 cases. •Includes one case of bilateral origin. tlncludes 2 cases of unspecified origin.
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The corresponding percentages at the Ochsner Clinic were 12, 49, and 39. How ever, at the Overholt Clinic, a greater percentage of tumors treated by lobectomy were in the right lung—61 per cent, contrasted with 41 per cent of those treated by pneumonectomy (Table V ) . There is no clear relationship between the location of the tumor and the 5-year survival rates. Adjustment for differences in the distribution of cases with respect to site of origin has virtually no effect on the survival rates for each of the three treatment groups. It is concluded that there is no demonstrable effect of tumor location on the relationship among the three groups. TABLE V I . FIVE-YEAR SURVIVAL R A T E S BY STAGE OF DISEASE, OPERATION, AND SIZE OF LESION : SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT) 5-YEAR SURVIVAL RATE
STAGE AND SIZE OF LESION
NO.
Localized All cases Small Medium Large Unspecified (Average size)
60 100 I s "30 23 38 17 28 2 3 (4.9 cin.)
Not Localized All cases Small Medium Large Unspecified (Average size)
PNEUMONECTOMY (OVERHOLT)
%
(%) 40 45 36 37
-
56 100
12
4 ~T
_
20 26 6
36 0 15 46 11 (0) (6.3 cin.)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE NO.
%
(%)
45 100 35 34 ~I3~" ""29" 12 27 32 19 12 27 8 18 (62) (4.9 cm.) 166 100 23 "14" 65 39 58 35 20 12 (5.7 cm.)
15 4 18 14 18
5-YEAR SURVIVAL RATE
%
(%)
49 100
39 (42) 43 38
NO.
9
21 15 4
U
43 31 8 (5.4 cm.)
142 100
~U TT' 57 56 13
40 39 10 (5.9 cm.)
7 "O 11 5 8
All Stages 15 19 191 100 All cases 27 116 100 211 100 25 "13 15 15 Small ~22" "19 36 ~TT "46 43 37 19 77 36 20 78 41 20 Medium 15 43 37 24 70 33 71 37 12 Large 8 7 28 13 31 17 9 Unspecified (12) 12 (5.6 cm.) (Average size) (5.6 cin.) (5.8 cm.) Note: (1)Percentages may not total 100 because of rounding. (2) Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases.
Size of Primary Tumor.—Measurements of the primary tumors in the resected lungs were examined for the possible effect of tumor size on prognosis, and for differences in the distribution of tumor size in the three operation groups. For purposes of presentation, the tumor measurements were divided into three categories of small (under 3 cm. in the largest diameter), medium (3.0 to 5.9 cm.), and large (6 cm. or over). Table V I summarizes these data. There is, at best, but a suggestion of an inverse relationship between size and survival in the Overholt resections of localized neoplasms, but none of the differences in survival rates are statistically significant, and no consistent relationships are evident in other groups. There was a slightly larger proportion of tumors classified as " s m a l l " in the Overholt
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than in the Ochsner series, but the distributions were not significantly different. Patients with localized disease had somewhat smaller tumors than patients with not-localized disease, but the analysis by stage showed no significant differences among the operation groups with respect to average tumor size. Standardization of the survival rates with respect to tumor size has no significant effect on the relationship among the three operation groups. There fore, there is no demonstrable evidence that the size of the primary tumor, in the range represented in these resections, influenced the survival rates or was an important factor of difference between the three operation groups. TABLE V I I .
FIVE-YEAR SURVIVAL RATES BY STAGE OF DISEASE, OPERATION, TYPE: SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
STAGE AND HISTOLOGIC TYPE
Localized All cases Epidermoid A denoearcinoma Undifferentiated Not Localized All cases Epidermoid Adenoearcinoma Undifferentiated
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE
%
(%)
100 45 42 13
40 50 34 (25)
56 100 ~22~ "39 17 30 17 30
12 l3~ 14 0
NO.
60 27 25 8
AND HISTOLOGIC
PNEUMONECTOMY (OCHSNER) 5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
%
(%)
45 29 6 10
100 64 13 22
35 38 (50) 20
166 85 27 54
100 51 16 33
15 19 12 9
NO.
All Stages 116 100 211 100 All cases 27 19 49 42 114 54 24 Epidermoid 38 42 36 33 Adenoearcinoma 26 16 19 25 64 22 8 Undifferentiated 30 11 Note: (1) Percentages may not total 100 because of rounding-. 5-9 cases shown in parentheses.
%
(%)
49 36 6 7
100 73 12 14
39 41 (50) 14
.142 30 27
100 60 21 19
7 13 0 1
191 121 36 34
100 63 19 18
15 21 8 3
NO.
~8F
(2) Rates based on
Histologic Type.—The tumors were classified into three categories with respect to histologic characteristics: (1) epidermoid or squamous cell carcinoma; (2) adenoearcinoma—this category includes 8 bronchiolar (alveolar) tumors in the Overholt series and 3 in the Ochsner series, and one malignant bronchial adenoma in the Overholt series; and (3) undifferentiated (anaplastic, pleomorphic) carcinoma—this category includes 2 oat cell tumors in the Overholt series and one in the Ochsner series. The findings by histologic type are given in Table VII. Tumors designated by pathologists as epidermoid were relatively more fre quent in the Ochsner series (63 per cent) than in the Overholt series (50 per cent). Tumors classified as undifferentiated were less frequent in the Ochsner series (18 per cent versus 27 per cent in the Overholt series). Survival at 5 years was rather uniformly low among patients with tumors of the undifferen tiated type in each treatment group. In this respect, the material is somewhat weighted against the Overholt series. Among both localized and not-localized
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cases there were relatively more adenocarcinomas in the lobectomy group than in the two pneumonectomy groups. In spite of the differences in the histologic distribution of cases within treatment groups, standardization of survival rates with respect to histology has little effect on the relationship among the three groups. Among localized cases, the histology-standardized rates were 42 per cent for the Overholt lobec tomy, 38 per cent for the Overholt pneumonectomy, and 39 per cent for the Ochsner pneumonectomy. The corresponding adjusted survival rates for notlocalized cases were 15, 15, and 7 per cent. TABLE V I I I .
STAGE AND AGE A T DIAGNOSIS
Localized All cases <50yr. 50-59 yr. 60-69 yr. 70+ yr. (Average age) Local ized All cases < 5 0 yr. 50-59 yr. 60-69 yr. 70+yr. (Average age)
FIVE-YEAR SURVIVAL BATES BY STAGE OF DISEASE, OPERATION, SURGICALLY TREATED LUNG CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956
AGE:
LOBECTOMY (OVERHOLT)
P N E U MONECTOM Y (OVERHOLT)
PNEUMONECTOMY (OCHSNER)
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL SATE
(%)
(%)
(%)
NO.
%
60 12 15 25 8
100 20 25 42 13
OB RELA SERVED TIVE*
40 46 56 33 (30)
47 47 61 40 (46)
NO.
%
45 5 15 23 2
100 11 33 51 4
^(60 years)
OB RELA SERVED TIVE*
35 40 43 31
39 41 47 38
-
-
NO.
49 12 18 14 5
(60 y ears)
% 100 24 37 29 10
OB RELA SERVED TIVE*
39 25 52 41 (20)
45 26 57 50 (30)
(57 years)
Not
56 9 18 19 10
100 16 32 34 18
12 11 17 12 0
(60 pears)
13 11 18 15 0
166 27 72 59 8
100 16 43 36 5
15 19 14 16 12
(58 years)
18 20 15 20 18
142 31 59 47 5
100 22 42 33 4
7 7 10 5 (0)
8 7 11 6 (0)
(57 years)
All Stages 19 All cases 116 100 27 31 211 100 23 191 100 15 17 32 12 12 22 15 23 43 23 21 33 34 < 5 0 yr. 18 50-59 yr. 87 41 19 21 77 33 28 35 38 40 20 22 60-69 yr. 44 38 24 29 82 39 20 25 61 32 13 16 70+ yr. 10 10 10 18 16 13 20 5 15 5 10 15 (Average age) (60 : (rears) (58 y ears) (57 years) Note: (1) Percentages may not total 100 because of rounding. (2) Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases. •Relative survival rates are obtained by adjusting the observed rates for normal life expectancy.
Effect of Age and Sex.—Table V I I I summarizes the effect of age on sur vival, by the relevant operation groups and extent of disease. The 327 patients in the Overholt series were somewhat older, with a mean age of 59 years; the mean age of 191 Ochsner patients was 57 years. The slight under-representation of older patients in the Ochsner group is in part due to the exclusion of 13 patients who were considered ineligible for pneumonectomy and on whom lobectomy was performed; their average age was 63 years. There is no consistent or significant effect of age on survival, particularly
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when the figures are adjusted for the expected mortality in each group and the relative survival figures derived. Upon age-adjusting the observed or relative rates, it is concluded that the age differences among various operation groups and the two clinics are not an important variable influencing survival. TABLE I X .
FIVE-YEAR SURVIVAL KATES BY STAGE OP DISEASE, OPERATION, AND S E X : SURGICALLY TREATED L U N G CANCER P A T I E N T S OCHSNER CLINIC, 1948-1956; OVERHOLT CLINIC, 1951-1956 LOBECTOMY (OVERHOLT)
PNEUMONECTOMY (OVERHOLT)
5-YEAR SURVIVAL RATE STAGE AND S E X
Localized All cases Male Female Not Localized All cases Male Female
(%)
NO.
%
(%)
60 100 49 82 11 18
40 41 40
43 2
96 4
35
56
12
166
100
16 0
151 15
91 9
15 15 7
44 12
100 79 21
5-YEAR SURVIVAL RATE
5-YEAR SURVIVAL RATE
%
NO.
PNEUMONECTOMY (OCHSNER)
%
(%)
43 6
88 12
39 (33)
142
100
124 18
87 13
7 8 0
NO.
All Stages All cases 116 100 211 100 19 27 191 100 15 93 194 92 Male 80 29 20 87 16 167 Female 12 13 23 19 17 24 20 8 8 Note: Rates based on 5-9 cases shown in parentheses; no rates shown for less than 5 cases.
The proportion of females in the Overholt and Ochsner series is almost identical—approximately 12.5 per cent in each. However, relatively more women were treated by lobectomy than by pneumoneetomy at the Overholt Clinic (Table I X ) . Among localized cases, survival among male and female patients was similar, but female rates were lower among not-localized cases. The number of female patients in this study is too small for a meaningful comparison with the survival experience of male patients. On a wider national basis, the survival of females was found to be better than of males, particularly among surgicallytreated localized cases.8 Sex adjustment of the survival rates for the three treatment groups left the rates virtually unchanged. I t is, therefore, concluded that sex differentials are not of sufficient importance to alter any prior conclusions. DISCUSSION
The data available from the Overholt and the Ochsner clinics on the treat ment and survival of patients with bronchogenic carcinoma were compared with similar data obtained from 99 hospitals in the United States, on over 8,800 cases, as reported by the End Results Group of the National Cancer Institute. 9 The end results are similar and emphasize the universally grim prognosis of this neoplastic disease. The broad experience of the 99 hospitals from 1950 to 1957 was as follows:
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SHIMKIN ET AL.
J. Thoracic and Cardiovas. Surg.
8,807 confirmed diagnoses of bronchogenic carcinoma were made; 29 per cent of these patients were surgically treated; 5-year survival in cases of resection was approximately 16 per cent, and among all patients was 6 per cent. From the findings of this and previously reported studies, 1 ' 6 resectability rates pertaining to the same period of time at the Overholt and Ochsner clinics were approximately 40 per cent; 5-year survival in all cases of resection was approximately 20 per cent; this represents a 5-year survival of about 8 per cent among all patients with bronchogenic carcinoma seen at these two clinics. This small salvage is achieved only by surgical resection. The point of this report is to analyze whether the type of surgical resection significantly affects the results. The available data lead to these conclusions: 1. Survival after surgical resection was primarily determined on whether the tumor was found to be localized or had extended to lymph nodes or con tiguous tissues beyond the lung. 2. Survival in patients with localized lung cancer was similar whether lobectomy or pneumonectomy was performed. The available evidence does not clearly delineate the efficacy of lymph node dissection. 3. Survival of patients with not-localized carcinomas was lower following pneumonectomy with mediastinal lymph node dissection than after more limited pneumonectomy or lobectomy. 4. Survival in these series was not demonstrably improved by the addition of x-ray therapy or chemotherapy with an alkylating agent. 5. Tumors classified as being histologically undifferentiated had a graver prognosis than the epidermoid neoplasms or the adenocarcinomas. 6. Survival was not demonstrably related to the size of the primary tumor, the site of the primary tumor within the lung, or the age and sex of the patient. It is difficult to accept the third conclusion, that a more limited surgical removal of a not-localized neoplasm produces more actual salvage than the more extended resection. The interpretation perforce is that the latter pro cedure not only has a higher immediate postoperative mortality but an in creased mortality over the whole 5-year postoperative course. More briefly and directly: the less extensive operations do not save more patients, but the more extensive operations increase mortality. It is essential to point out that no extrapolations beyond the data and their limitations are possible. An attempt was made to measure the effect of such factors as histologic type, size and location of the lesion, and the age and sex of the patients on the survival rates for the three treatment groups. Treating each factor independently, no significant effect was demonstrated. However, this does not mean that some combination of factors may not affect survival. The series at hand is too small to permit this type of an analysis. Furthermore, although the evidence suggests that lobectomy with regional lymph node removal is an adequate operation for patients with neoplasms surgically circumscribable by this procedure, it does not follow that even more limited operations may be desirable. On the other hand, such procedures in combination with, say, preoperative x-ray therapy, may be worth considering for controlled clinical trials.
Vol. 44, No. 4
BEONCHOGENIC CARCINOMA
519 UXJ
October. 1962
The tragic limitations of effective treatment of bronchogenic carcinoma, and the established causation of an important proportion of this neoplasm bycigarette smoking, make the disease a challenge to preventive medicine as well as to cancer research. SUMMARY
The survival experience of lung cancer patients treated surgically at the Ochsner and Overholt clinics has been analyzed in order to evaluate the relative merits of lobectomy and pneumonectomy. Available for the main analysis were 116 Overholt lobectomies, 211 Overholt pneumoneetomies, and 191 Ochsner pneumonectomies. Among the localized cases, the 5-year survival rates for the above-mentioned groups were not significantly different, being 40, 35, and 39 per cent, respectively. Analyses carried out on the possible affect of various factors which might in fluence survival revealed differences of such degree and direction so as not to alter this conclusion. Among not-localized cases, the 5-year survival rates for the three groups were 15, 12, and 7 per cent, respectively. The significant difference in survival between the Overholt and Ochsner pneumonectomy groups was mainly asso ciated with extent of lymph node dissection. Among those Overholt and Ochsner patients treated by pneumonectomy with mediastinal lymph node dissection, the operation usually performed at the Ochsner Clinic, the survival rates were very similar, 9 and 7 per cent, respectively. However, at the Overholt Clinic, a group of 56 patients undergoing pneumonectomy with dissection of only the hilar nodes had a survival rate of 25 per cent. The clinical significance of the above differences were difficult to evaluate since the considerations which led to the use of more extensive surgery in some cases and less extensive surgery in others were not fully known. However, the available evidence suggests that less extensive surgical procedures were related to survival rates that were at least as good as, and perhaps better than, those recorded following more extensive surgery. REFERENCES
1. Overholt, R. H., and Bougas, J . A . :
Common Factors in Lung Cancer Survivors, J .
THORACIC SURG. 32: 508-517, 1956.
2. Lawrence, G. H., Walker, J . H., and Pinkers, L . : Extended Resection of Bronchogenic Carcinoma: A Reappraisal and Suggested Plan of Management, New England J . Med. 263: 615-620, 1960. 3. Jones, J . C , Robinson, J . L., Meyer, B . W., and Motley, H . L . : Primary Carcinoma of the Lung. A Follow-up Study Involving Pulmonary Function Studies of Long-Term Survivors, J . THORACIC SURG. 39: 144-158, 1960.
4. Overholt, R. H . : The Surgical Treatment of Bronchogenic Cancer, Proc. Fourth National Cancer Conference, Philadelphia, 1960, J . B . Lippincott Co., p p . 309-314. 5. Ochsner, A., Ray, C. J., and Acree, P . W . : Cancer of the Lung, Am. Rev. Tuberc. 70: 263-259, 1954. 6. Ochsner, A., Ochsner, A., J r . , H 'Doubler, C , and Blalock, J . : Bronchogenic Carcinoma, Dis. Chest 3 7 : 1-12, 1960. 7. Cutler, S. J., and Ederer, F . : Maximum Utilization of the Life Table Method in Analyzing Survival, J . Chron. Dis. 8: 699-712, 1958. 8. Mersheimer, W. L., and Ederer, F . : E n d Results Evaluation of Cancer of the Lung and the Bronchus, Proc. Fourth National Cancer Conference, Philadelphia, 1960, J . B. Lippincott Co., p p . 319-322. 9. End Results and Mortality Trends in Cancer, National Cancer Institute Monograph No. 6, Washington, D. C , TJ. S. Gov't Printing Office, 1961.