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Factors influencing survival after resection for bronchial carcinoma
Factors influencing survival after resection for bronchial carcinoma Thomas W. Shields, M.D., Chicago, III., George A. Higgins, M.D. (by invitation), and Robert J. Keehn, M.S. (by invitation), Washington, D. C.
Ihe Veterans Administration Surgical Adjuvant Cancer Chemotherapy Study Group has conducted a series of clinical studies to evaluate the use of selected drugs as surgical adjuvants in the treatment of bronchial carcinoma. In September of 1957, the first patient with carcinoma of the lung was entered into the nitrogen mustard trial. Five different protocols were in effect during the next 10 years, and, while the therapy under study changed, the criteria for accepting patients for the study remained almost constant. As a result, data on a large number of male patients who underwent resection for previously untreated primary bronchial carcinoma have been assembled. Patients with previously diagnosed tumors of other organ systems, those with lesions classified as bronchiolar or alveolar cell carcinoma, and those with active tuberculosis or a bronchial adenoma were specifically excluded by the protocols. At the end of the operation, the patients were classified as having either a curative or palliative resection, deFrom the Veterans Administration Surgical Adjuvant Cancer Chemotherapy Study Group.* Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972. Address for reprints: Thomas W. Shields, M.D., Veterans Administration Research Hospital, 333 East Huron Street, Chicago, IU. 60611. •Contributors to this study are listed at the end of this article.
pending upon whether all apparent tumor had been removed. Although resection is considered to be the most effective treatment for bronchial carcinoma, the survival rate 5 years after resection for cure is discouragingly low, generally reported to be below 25 per cent. We studied 5 year survivors as well as patients who died, especially if they died in the first 30 postoperative days, in an effort to identify those characteristics of the patient and of the disease which are associated with survival. In an initial review of 933 patients with carcinoma of the lung who had undergone resection in the Veterans Administration studies, Higgins and Beebe 1 noted that the age of the patient, presence of significant nonpulmonary disease, extent of resection, and site of operation were important factors in the 30 day postoperative mortality rate. The major factors influencing long-term survival were the extent of the disease as determined by study of the resected specimen and, interestingly, the age of the patient. Neither the cell type nor the size of the tumor was found to be significant. In order to re-evaluate the validity of some of the original conclusions concerning the factors influencing long-term survival, an additional 870 patients with carcinoma of the lung who have undergone resection have been added to the original 933 patients studied by Higgins and Beebe.1 39 1
392
The Journal of
Shields, Higgins, Keehn
Thoracic and Cardiovascular
Surgery
Table I. Summary of patient evaluation Number
Per cent
1,803
100.0
1,370 433
76.0 24.0
1,370
100.0
294 33 37
21.5 2.4 2.7
Total living
364
26.6
Dead, no evidence of cancer Dead, with cancer Dead, unknown for cancer
2491 621 136
18.2 45.3 9.9
Total patients Date of resection On or before Dec. 31, 1964 Jan. 1, 1965 or later* Patients evaluated 5 years postoperatively Status of patients Alive, no evidence of cancer Alive, with cancer Alive, unknown for cancer
Total dead
1,006
73.4
♦Resection performed less than 5 years prior to the cutoff date for receipt of records used in analysis. tlncludes 209 patients for whom the absence of cancer was established by autopsy.
Material and method of study This report is based upon an analysis of data obtained from 1,803 patients who were considered to have no residual disease at the completion of the operative procedure— so-called curative resection. Of these, 1,370 patients or 76 per cent had undergone resection 5 years or more prior to the cutoff date for the receipt of records used in the analysis (Table I ) . Patients accepted for study were subject to re-examination at 3 month intervals for 2 years and at 6 month intervals thereafter for the detection of recurrent disease. While the completeness of clinical follow-up information varied considerably from one patient to another, data regarding survival was virtually complete because of the systemwide index of veterans maintained by the Veterans Administration. These observations were the basis for determining the primary measure of success used in the analysis, i.e., that the patient was alive and apparently free of disease 5 years postoperatively. The search for variables predictive of outcome was directed to this subgroup of pa-
tients whose follow-up for 5 years postoperatively was complete. At the fifth postoperative year, 364 patients were still living (26.6 per cent of the patients who underwent a curative resection). Of these surviving patients, 294 (81 per cent) were classified as free of cancer and 33 (9 per cent) as having recurrent cancer; in 37 (10 per cent), the presence of cancer was unknown. For patients who died within 5 years of resection, the presence of recurrent disease was based upon autopsy findings and upon available clinical information if an autopsy was not performed. Of the 1,006 patients who were dead at 5 years, 621 patients (62 per cent) were classified as having recurrent disease and 249 patients (25 per cent) were apparently free of disease; in 136 patients (14 per cent), the presence of cancer was unknown. Living and dead patients whose cancer status was unknown and patients who died without recurrence were not used in establishing the predictive importance of the characteristics studied, in order that attention be specifically directed to failures due to the recurrence of disease. Outcome was coded zero for patients who were alive and free of cancer at the fifth postoperative year and one if the disease had recurred. Thirteen characteristics which Higgins and Beebe1 earlier found to be significantly associated with cancer-free survival were examined for their independent prognostic importance (Table I I ) . Stepwise multiple regression was used in the analysis. In this method of analysis, one seeks to separate the interrelated contributions of a number of factors such as age, other concurrent pulmonary disease, and observations related to stage of disease at operation, ordering the factors by relative prognostic importance and assigning to each a numerical value or contribution to a patient's predictive score. The purpose of this score is to establish at operation the prospect for the patient's having been cured of his disease. Having derived prognostic scores for patients who have undergone a curative opera-
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tion, it was then necessary to evaluate how well these scores actually predicted whether disease would recur within 5 years. The relationship between the predictive scores and what actually happened to the patients was determined by means of the correlation coefficient. The degree of concurrence between the predictive score and actual outcome may be represented by a number ranging in value from minus one to plus one. Plus one correlation represents perfect agreement, and a coefficient of zero represents the total absence of an association between the prediction and the observed outcome.* The patients used in the analysis were subdivided by date of operation, so that a system of scoring derived from each group of patients could be tested with the other group. The earlier period, September, 1957, to June 15, 1960, defines one group; these represent the patients who were included in the earlier analysis of cancer-free survival at 5 years by Higgins and Beebe.1 The second group consists of patients who underwent operation from June 16, 1960, through Dec. 31, 1964. Results Predictive scores. The performance of scores in predicting outcome 5 years postoperatively for combinations of patients who were used in deriving and in testing the scoring systems have been compared (Table III). The scores were computed with the use of information for all thirteen variables. The best performance, correlation coefficients (r) about 0.3, was obtained when the same patients were used to derive the scoring system and test the resultant scores. Score performance was substantially poorer when tests were performed with different patients, the correlation coefficients being reduced to less than 0.2. While this represents a low level of association from *A prognostic score can be expected to provide the closest association with outcome for that particular group of patients used in the development of the scoring system. A more meaningful test of a scoring system is its performance when applied to a different group of patients.
Table II. Relationship of thirteen characteristics to 5 year cancer -free postoperative survival
Characteristics
Effect of characteristic upon cancer-free survival
Weight loss of 10 pounds or more Age under 60 years Physical evidence of cancer Other pulmonary disease Operation on right Pneumonectomy done Obstruction of bronchus Blood vessel invasion Lymphatic invasion Lobar node involvement Hilar node involvement Mediastinal node involvement Tumor confined to the lung
Unfavorable Favorable Unfavorable Unfavorable Favorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Favorable
the standpoint of predicting outcome for individual patients, the association is clearly greater than could be expected due to chance. The score system derived from the experience of all patients was clearly best from the standpoint of consistency of performance with the two test groups. It is interesting that this consistency of performance was achieved while a relatively high level of association between score and outcome was maintained. The performance of the scores was not appreciably affected when the number of variables was successively reduced from thirteen to the eight and then to the four most important variables (Table I V ) . The only observed gain in score performance, with the use of more than four variables in scoring, was seen in the patients with more recent operations. However, the increase in the correlation of score with outcome, 0.235 to 0.268, was too small to indicate that a real difference in score performance exists. The four-variable score for predicting cancer-free survival is calculated for a patient by adding the following numerical values: limited to the lung, zero, and extend-
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Table III. Correlation of predictive scores based upon the thirteen characteristics with observed outcome Patients used in deriving scoring Patients
used in testing scores
No. of
patients
Early experience
Total experience
Late experience
Early experience Late experience
304 362
Correlation 0.315* 0.174
Total
666
0.237
values
of score and 0.154 0.304*
outcome 0.275 0.268
0.235
0.270*
Legend: Early experience includes those patients operated upon in the period from September, 1957, to June 15, 1960. Late experience includes those operated upon in the period from June 16, 1960, to December, 1964. •Coefficients which resulted when the same patients were used to derive the scoring values and test the resultant scores.
Table IV. Correlation of predictive scores derived from the total patient experience with observed outcome Patients used in testing scores
Number of variables used in scoring patients Four*
Eight!
Thirteen
Score
No. of patients
Per cent
in test
Under 0.20 0.20-0.29 0.30-0.39 0.40-0.49 0.50 and over
115 231 230 101 90
54.8 39.8 26.5 23.8 12.2
Total
767
32.7
Number
of patients
Early experience Late experience
341 426
327 398
304 362
Total
767
725
666
Early experience Late experience Total
Correlation of score and outcome 0.309 0.299 0.275 0.235 0.263 0.268 0.268
0.278
Table V. Percentage of patients alive and cancer free by predictive scores based upon four variables and derived from the total patient experience
0.270
♦The four variables were tumor extending beyond the lung, age at randomization, involvement of mediastinal lymph nodes, and other pulmonary disease. fThe eight variables included the four variables plus blood vessel invasion, resection on the right side, physical evidence of cancer, and lymphatic invasion.
ing beyond the lung, 0.1675; age at randomization, age times 0.00353; mediastinal lymph nodes not involved, zero, and involved, 0.1389; other pulmonary disease not found, zero, and found, 0.1135. The score is designed so that an increase in score value signifies an increase in the probability that the disease will recur, or a decrease in the percentage of patients living and cancer free at 5 years (Table V ) . No score fell below 0.10 (the score of a 28year-old patient with no unfavorable indications), nor did any score exceed 0.68
(the score of a 74-year-old patient with tumor extending beyond the lung, with mediastinal nodes involved, and with another pulmonary disease). Percentages of patients alive and free of cancer at 5 years vary from 54.8 per cent in patients with scores less than 0.20 to 12.2 per cent for patients with scores of 0.50 or more. The effects of specific combinations of the predictive variables and the percentage of cancer-free survival are shown in Table VI. The most important factor from the standpoint of influence upon the 5 year cure rate is extension of the tumor beyond the lung, a finding which is associated with a decrease of 17 of the 5 year cures per 100 patients who have undergone resection. An age of 60 years or more appears to be a more important observation in patients with tumor that is confined to the lung. The effects of tumor in the mediastinal nodes
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Resection for bronchial carcinoma
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Table VI. Percentage of patients alive and cancer free 5 years postoperatively for combinations of the four most predictive variables
Combination
Tumor limited to lung; age under 60 years
o f variable
Tumor limited to lung; age 60 years and over
Tumor Tumor beyond lung; beyond lung; age under age 60 years and over 60 years
Percentage alive and cancer free after 5 years* Mediastinal nodes not involved; no other pulmonary disease found Mediastinalnodes not involved; another pulmonary disease found Mediastinal nodes involved; no other pulmonary disease found Mediastinal nodes involved; another pulmonary disease found
51.9 (129)
39.5 (205)
28.6 (112)
24.6 (142)
47.1 (17)
34.1 (44)
0.0 (7)
13.8 (29)
14.3 (26)
24.1 (48)
33.3 (3)
0.0 (5)
'Figures in parentheses indicate numbers of patients in each group.
upon recurrence appears to vary, possibly due to small numbers; the average effect is a decrease of 14 cures per 100 patients. The presence of another pulmonary disease is associated with 11 fewer cures per 100 patients. Survival. Only patients who underwent operation prior to January, 1965, enabling them to be in the study at least 5 years as of January, 1970, were used in the analysis for the identification of factors predictive of outcome following a curative resection for lung cancer. However, the use of life-table procedures permitted all 1,803 patients with curative procedures through December, 1967, to be included in the study of postoperative survival. Postoperative survival curves have been computed for 752 patients with four-variable prognostic scores of less than 0.325 (more favorable), for 696 patients with scores of 0.325 or more (less favorable), and for the 355 patients whose scores were not computed because of incomplete information (Fig. 1). Patients with lower scores had a survival rate of 37 per cent at 5 years and 24 per cent at 10 years postoperatively, compared with 19 and 11 per cent, respectively, for patients with higher scores. The curve for patients with unknown scores, discontinued at 9 years postoperatively because too few patients were still
under observation, lies between the curves for patients with lower and higher scores but resembles the latter more closely. A question remains as to whether the mortality rate following a curative resection for lung cancer eventually returns to normal. One can estimate the number of deaths expected during each successive postoperative year by applying age-specific death rates for United States males to observed survivors. The relative risk of death, i.e., the number of deaths observed for each expected death, can then be used as a measure of the level of mortality following curative operation. The results have been summarized as average annual relative risks for remaining years of follow-up (Fig. 2 ) . The observed average annual death rate was 8.2 times expectation when computed from operation, declined to 1.9 times expectation for follow-up beyond the seventh postoperative year, and then increased with each succeeding year of follow-up, reaching 3.9 beyond 10 postoperative years. A similar analysis was repeated for highscore and low-score patients (Fig. 3). The average annual relative risk of death from operation was 9.8 for high-score patients compared to 6.4 for those with low scores, but both risks declined to 3 at 4 years after operation and remained about the same through 8 years postoperatively. Too few
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100 752 Patients with more fawrable scores 696 Patients with less favorable scores ■355 Patients without scores
8 9 10 3 4 5 6 7 Completed Postoperative Years Fig. 1. Per cent of survivors following curative surgery for bronchial carcinoma. Patients grouped by magnitude of four-variable score predictive of outcome relative to mean score.
0
1
2
rr
I
2
3
4
5
6
7
10
Completed Postoperative Years
P(RR«1)<.0001<0001<0001<.0001<.0001<.0001<.0001 .02 .02 .05 07 Fig. 2. Average annual relative risk of death during remainder of follow-up for patients with curative surgery for bronchial carcinoma. Expected mortality rate, based upon age-specific death rates for United States males and actual survivors at risk each year, equals unity. The area between 95 per cent confidence limits is shaded. RR, Relative risk.
patients have been followed beyond 8 years to attach any significance to the subsequent divergence of relative risks. Discussion In the present evaluation of the long-term survival of male patients with bronchial carcinoma who have undergone a curative resection, the major factor influencing such survival was the extent of the tumor at the
time of the resection. If the tumor was confined to the lung, long-term survival was a much greater possibility than if the tumor had spread to adjacent lymph nodes or to contiguous structures. A second but less important factor was the age of the patient; this had an adverse effect especially in patients with tumor confined to the lung who were 60 years of age or over. The presence of mediastinal node involvement and the
Volume 64 Number 3 September, 1972
Resection for bronchial carcinoma
10
9 8
\ \ \ \ \
397
752 Patients with more favorable scores "696 Patients with less favorable scores
7
6 to
Q
15
5 4 3
.5 0
♦Relative risks differ significantly P< .001. P > 05 for remaining comparisons.
1
2
3
4
5
6
7
8
9
10
Completed Postoperative Years RdffX.000K.0001
.0002
.18
.09
.91
.83
.84
.28
.69
Fig. 3. Average annual relative risk of death during remainder of follow-up by four-variable predictive score. Expected mortality rate equals unity.
presence of another pulmonary disease also adversely affected long-term survival. Actually, the derived four-variable predictive score was more efficient in predicting a treatment failure than in predicting longterm survival. This is readily understandable since, even with a grossly localized tumor, occult distant metastases may well be present. The failure of cell type and the size of the tumor to influence long-term survival in this series of patients remains somewhat difficult to explain. This is especially true since these factors did influence prognosis in the cases recently reported by Slack.2 In the series that he reported, the prognosis decreased with the increase in the tumor size. Also, the best prognosis was associated with the presence of a bronchiolar cell carcinoma and the poorest with an anaplastic tumor; in between these two extremes were the adenocarcinoma and the squamous cell tumors, for which the prognosis was about equal. However, it should be remembered that in regard to cell types, the two series are not comparable since, in the present Veterans Administration study, patients with bronchiolar cell carcinoma were excluded. Furthermore, women, who have a somewhat different incidence of the various
cell types than men have, likewise were excluded from the study. These two exclusions must be considered to have an effect on the relative significance of the influence of cell type in the present study. Furthermore, it should be noted that our usual understanding of the relationship of cell type to prognosis is based primarily upon the study of all patients with the disease. As a result, the entire clinical spectrum of the various lesions comes under consideration and, in this situation, the cell type of the tumor is of prognostic importance. On the other hand, the patients in the present series are highly selected; only those with lesions thought to have been totally removed at operation are included in the study. As a result, the significance of cell type may be lost readily in such a selected group of patients. It should be noted that patients with squamous cell carcinoma did fare somewhat better, as also reported by Higgins and Beebe.1 However, the finding was not statistically significant. As with the lack of significance of cell type, the lack of influence of tumor size may only reflect exclusion of the bronchiolar cell tumors or the inappropriate collection of relevant data from study of the operative specimen.
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Summary Patients in the Veterans Administration Surgical Adjuvant Cancer Chemotherapy trials who had curative resections, i.e., clinically no residual disease, during the first 10 years of study were evaluated for factors predictive of recurrence within 5 years of the operation. Thirteen characteristics which, in an earlier study, were found to be significantly associated with cancer-free survival 5 years postoperatively were reexamined in an effort to improve the ability to predict outcome on the basis of information available at operation. In order to restrict attention to failures due to the recurrence of disease, patients whose status for recurrence at 5 years postoperatively could not be determined were excluded from the analysis. The thirteen variables were examined for independent predictive information by means of stepwise multiple regression. Numerical values were assigned to each variable, with the sum for a patient being his predictive score. These derived scores were correlated with coded observed outcome (zero for success and one for failure) for a measure of association. The degree of association was greater—correlation coefficients (r) = 0.3—when the same group of patients used to derive the numerical values of observations was used to correlate computed scores with observed outcome; the degree of association was smallest but still statistically significant—r > 0.2—when a completely different group of patients was used to test the association of prediction and outcome. However, these associations are too low to permit accurate predictions for individual patients. The thirteen variables contain a substantial amount of shared predictive information. Restriction of prognostic scores to information carried by the eight or the four more important variables produced little, if any, reduction in the association of score with observed outcome. Predictions of outcome were equally good when based upon age of the patient and extension of the
Thoracic and Cardiovascular Surgery
tumor beyond the lung, involvement of mediastinal nodes, and the presence of another pulmonary disease. Four-variable scores defined categories of patients with prospects for 5 year cancer-free survival ranging from a high of 55 per cent to a low of 12 per cent. Four-variable scores were computed for 1,448 of the 1,803 patients with curative surgery in the study, and survival curves were computed. There were 752 patients whose scores were less than the mean score (0.325), thus more favorable, and 696 patients with scores equal to or greater than the mean, thus less favorable. In 355 patients, information was missing for one or more of the four variables, and thus a predictive score could not be computed. Survival rates in patients with the more favorable scores were 37 per cent at 5 years and 24 per cent at 10 years, compared with 19 and 11 per cent, respectively, in patients with less favorable scores. Survival rates in patients with unknown scores were slightly above those for patients with the less favorable scores. Average annual relative risks of death, i.e., the average number of observed deaths per remaining year of follow-up for each expected death, based upon age-specific death rates for the United States male population, was highest (8.2) at operation and lowest (1.9) beyond the seventh completed year of follow-up. The relative risk of death appeared to rise after 7 years of follow-up and significantly exceeded unity after 9 years. Too few patients were followed beyond the seventh postoperative year to conclude that the increase in relative risk was not due to chance. REFERENCES 1 Higgins, G. A., and Beebe, G. W.: Bronchogenic Carcinoma, Arch. Surg. 94: 539, 1967. 2 Slack, N. H.: Bronchogenic Carcinoma, Cancer 25: 987, 1970.
Appendix Principal investigators. George A. Higgins, Jr., Chairman, Washington, D. C ; Richard W. Dwight, Boston, Mass.; Philip Cooper, Bronx, N. Y.; Harry H. LeVeen, Brooklyn, N. Y.; Thomas W. Shields,
Volume 64 Number 3 September, 1972
Site Chairman, Chicago, 111.; Carl G. Schowengerdt, Cincinnati, Ohio; Jerry S. Wolkoff, Cleveland, Ohio; Robert Hays, Dallas, Texas; Oscar Serlin, East Orange, N. J.; William S. Walsh, Hines, 111.; Paul Jordan, Houston, Texas; Richard L. Lawton, Iowa City, Iowa; J. Harold Conn, Jackson, Miss.; Alfred Heilbrunn, Kansas City, Mo.; George L. Juler, Long Beach, Calif.; Edward W, Humphrey, Minneapolis, Minn.; James Yee, Martinez, Calif.; Stanley J. Dudrick, Philadelphia, Pa.; Adolph J. Yates, Pittsburgh, Pa.; Harold W. Harrower, Providence, R. I.; Jose H. Amadeo, San Juan, P. R.; Robert C. Donaldson, St. Louis, Mo.; Lloyd S. Rogers, Syracuse, N. Y.; Gale L. Mendeloff, Wood, Wis. Coordinator. Lyndon E. Lee, Jr., Associate Chief Medical Director for Professional Services, Department of Medicine and Surgery, Veterans Administration Central Office. Statistician. Robert J. Keehn, Follow-up Agency, National Academy of Sciences, National Research Council.
Discussion DR. R I C H A R D H. O V E R H O L T Boston,
Mass.
Dr. Shields and his co-authors have reduced the number of prediction factors for survival with cancer of the lung from thirteen down to four. In a retrospective study of close to 300 patients who have been cured in our series, we can find only three common denominators. First, all of these patients had an abnormal shadow on the x-ray film to lateralize the disease. Second, none of them had evidence of hematogenous dissemination. Third, almost all had been treated by surgical resection. It was the rare patient who had been treated by x-ray therapy alone and had survived 5 years. Curability seems to be in reverse proportion to the ease of histologic verification, other than surgical exploration. Chances for long-term survival are best when the lesion cannot be seen bronchoscopically, when bronchial secretions are negative for tumor cells, and when cervical and mediastinal nodes fail to settle the issue. [Slide] We reviewed 100 consecutive cases in which surgery indicated that the cancer apparently was localized. A fourth of these cases had been discovered by survey. Only 40 patients had preoperative histologic proof of cancer. Therefore, in 60 per cent of these most favorable situations, the issue was settled by a total biopsy which simultaneously provided the most promising therapy. It has been our hope that, as the years passed, more "silent" lesions would be discovered.
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[Slide] Dr. Francis Woods has recently reviewed our survey cases and has found that, up to 1955, only 4.2 per cent of all the cases were discovered by survey. However, in the last 10 years the incidence of survey among the total group has risen to 9 per cent, with an increase in resectability. As the authors have pointed out, the histologic type does not influence the survival rate exactly. However, the localization process has a greater importance at the time of incision. In our survey group, the number of undifferentiated lesions was only slightly less than the number of others. [Slide] Dr. Shields has stressed the importance of other factors in other pulmonary disease. It is ironic that the tars in inhaled cigarette smoke, which fertilize the cancer, also create chemical bronchitis and structural changes within the lung (emphysema) which remain after the operation. The smoke distribution and the damage is bilateral. The burden is not just at the portal of entry. Nicotine is in the smoke as well as tars. What this chronic poison has done to the circulatory system also relates to survival in the lung cancer patient. Therefore, we advise all patients of these multiple hazards, and we emphasize that pulmonary and circulatory function is so necessary to the duties as well as the pleasures of life that the crime of squandering it is equal to the folly. DR. T H O M A S W. S H I E L D S (Closing) I would like to thank Dr. Overholt for his remarks. In regard to cell type, there was a slight increase in survival in those patients who had squamous cell carcinoma over those who were classified in this particular study as having adenocarcinoma or undifferentiated cell types. However, the increase in survival was not statistically significant. I also might mention that the oat cell tumors were grouped into the undifferentiated category. This included a relatively small group of patients. In separating out the oat cell tumors, which were peripheral in location and only discovered at the time of frozen section analysis at operation, we found that 9.4 per cent of the patients who received Cytoxan postoperatively survived for 5 years, whereas only 3.8 per cent of the patients who received no other treatment survived that long. I believe that the significance of tumor size may well reflect the different locations of the various tumors (whether it was peripheral or whether it was central in location) as well as the effects of bronchial obstruction. As a result, tumor size per se is a difficult parameter to evaluate.
Ihe Veterans Administration Surgical Adjuvant Cancer Chemotherapy Study Group has conducted a series of clinical studies to evaluate the use of selected drugs as surgical adjuvants in the treatment of bronchial carcinoma. In September of 1957, the first patient with carcinoma of the lung was entered into the nitrogen mustard trial. Five different protocols were in effect during the next 10 years, and, while the therapy under study changed, the criteria for accepting patients for the study remained almost constant. As a result, data on a large number of male patients who underwent resection for previously untreated primary bronchial carcinoma have been assembled. Patients with previously diagnosed tumors of other organ systems, those with lesions classified as bronchiolar or alveolar cell carcinoma, and those with active tuberculosis or a bronchial adenoma were specifically excluded by the protocols. At the end of the operation, the patients were classified as having either a curative or palliative resection, deFrom the Veterans Administration Surgical Adjuvant Cancer Chemotherapy Study Group.* Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972. Address for reprints: Thomas W. Shields, M.D., Veterans Administration Research Hospital, 333 East Huron Street, Chicago, IU. 60611. •Contributors to this study are listed at the end of this article.
pending upon whether all apparent tumor had been removed. Although resection is considered to be the most effective treatment for bronchial carcinoma, the survival rate 5 years after resection for cure is discouragingly low, generally reported to be below 25 per cent. We studied 5 year survivors as well as patients who died, especially if they died in the first 30 postoperative days, in an effort to identify those characteristics of the patient and of the disease which are associated with survival. In an initial review of 933 patients with carcinoma of the lung who had undergone resection in the Veterans Administration studies, Higgins and Beebe 1 noted that the age of the patient, presence of significant nonpulmonary disease, extent of resection, and site of operation were important factors in the 30 day postoperative mortality rate. The major factors influencing long-term survival were the extent of the disease as determined by study of the resected specimen and, interestingly, the age of the patient. Neither the cell type nor the size of the tumor was found to be significant. In order to re-evaluate the validity of some of the original conclusions concerning the factors influencing long-term survival, an additional 870 patients with carcinoma of the lung who have undergone resection have been added to the original 933 patients studied by Higgins and Beebe.1 39 1
392
The Journal of
Shields, Higgins, Keehn
Thoracic and Cardiovascular
Surgery
Table I. Summary of patient evaluation Number
Per cent
1,803
100.0
1,370 433
76.0 24.0
1,370
100.0
294 33 37
21.5 2.4 2.7
Total living
364
26.6
Dead, no evidence of cancer Dead, with cancer Dead, unknown for cancer
2491 621 136
18.2 45.3 9.9
Total patients Date of resection On or before Dec. 31, 1964 Jan. 1, 1965 or later* Patients evaluated 5 years postoperatively Status of patients Alive, no evidence of cancer Alive, with cancer Alive, unknown for cancer
Total dead
1,006
73.4
♦Resection performed less than 5 years prior to the cutoff date for receipt of records used in analysis. tlncludes 209 patients for whom the absence of cancer was established by autopsy.
Material and method of study This report is based upon an analysis of data obtained from 1,803 patients who were considered to have no residual disease at the completion of the operative procedure— so-called curative resection. Of these, 1,370 patients or 76 per cent had undergone resection 5 years or more prior to the cutoff date for the receipt of records used in the analysis (Table I ) . Patients accepted for study were subject to re-examination at 3 month intervals for 2 years and at 6 month intervals thereafter for the detection of recurrent disease. While the completeness of clinical follow-up information varied considerably from one patient to another, data regarding survival was virtually complete because of the systemwide index of veterans maintained by the Veterans Administration. These observations were the basis for determining the primary measure of success used in the analysis, i.e., that the patient was alive and apparently free of disease 5 years postoperatively. The search for variables predictive of outcome was directed to this subgroup of pa-
tients whose follow-up for 5 years postoperatively was complete. At the fifth postoperative year, 364 patients were still living (26.6 per cent of the patients who underwent a curative resection). Of these surviving patients, 294 (81 per cent) were classified as free of cancer and 33 (9 per cent) as having recurrent cancer; in 37 (10 per cent), the presence of cancer was unknown. For patients who died within 5 years of resection, the presence of recurrent disease was based upon autopsy findings and upon available clinical information if an autopsy was not performed. Of the 1,006 patients who were dead at 5 years, 621 patients (62 per cent) were classified as having recurrent disease and 249 patients (25 per cent) were apparently free of disease; in 136 patients (14 per cent), the presence of cancer was unknown. Living and dead patients whose cancer status was unknown and patients who died without recurrence were not used in establishing the predictive importance of the characteristics studied, in order that attention be specifically directed to failures due to the recurrence of disease. Outcome was coded zero for patients who were alive and free of cancer at the fifth postoperative year and one if the disease had recurred. Thirteen characteristics which Higgins and Beebe1 earlier found to be significantly associated with cancer-free survival were examined for their independent prognostic importance (Table I I ) . Stepwise multiple regression was used in the analysis. In this method of analysis, one seeks to separate the interrelated contributions of a number of factors such as age, other concurrent pulmonary disease, and observations related to stage of disease at operation, ordering the factors by relative prognostic importance and assigning to each a numerical value or contribution to a patient's predictive score. The purpose of this score is to establish at operation the prospect for the patient's having been cured of his disease. Having derived prognostic scores for patients who have undergone a curative opera-
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tion, it was then necessary to evaluate how well these scores actually predicted whether disease would recur within 5 years. The relationship between the predictive scores and what actually happened to the patients was determined by means of the correlation coefficient. The degree of concurrence between the predictive score and actual outcome may be represented by a number ranging in value from minus one to plus one. Plus one correlation represents perfect agreement, and a coefficient of zero represents the total absence of an association between the prediction and the observed outcome.* The patients used in the analysis were subdivided by date of operation, so that a system of scoring derived from each group of patients could be tested with the other group. The earlier period, September, 1957, to June 15, 1960, defines one group; these represent the patients who were included in the earlier analysis of cancer-free survival at 5 years by Higgins and Beebe.1 The second group consists of patients who underwent operation from June 16, 1960, through Dec. 31, 1964. Results Predictive scores. The performance of scores in predicting outcome 5 years postoperatively for combinations of patients who were used in deriving and in testing the scoring systems have been compared (Table III). The scores were computed with the use of information for all thirteen variables. The best performance, correlation coefficients (r) about 0.3, was obtained when the same patients were used to derive the scoring system and test the resultant scores. Score performance was substantially poorer when tests were performed with different patients, the correlation coefficients being reduced to less than 0.2. While this represents a low level of association from *A prognostic score can be expected to provide the closest association with outcome for that particular group of patients used in the development of the scoring system. A more meaningful test of a scoring system is its performance when applied to a different group of patients.
Table II. Relationship of thirteen characteristics to 5 year cancer -free postoperative survival
Characteristics
Effect of characteristic upon cancer-free survival
Weight loss of 10 pounds or more Age under 60 years Physical evidence of cancer Other pulmonary disease Operation on right Pneumonectomy done Obstruction of bronchus Blood vessel invasion Lymphatic invasion Lobar node involvement Hilar node involvement Mediastinal node involvement Tumor confined to the lung
Unfavorable Favorable Unfavorable Unfavorable Favorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Unfavorable Favorable
the standpoint of predicting outcome for individual patients, the association is clearly greater than could be expected due to chance. The score system derived from the experience of all patients was clearly best from the standpoint of consistency of performance with the two test groups. It is interesting that this consistency of performance was achieved while a relatively high level of association between score and outcome was maintained. The performance of the scores was not appreciably affected when the number of variables was successively reduced from thirteen to the eight and then to the four most important variables (Table I V ) . The only observed gain in score performance, with the use of more than four variables in scoring, was seen in the patients with more recent operations. However, the increase in the correlation of score with outcome, 0.235 to 0.268, was too small to indicate that a real difference in score performance exists. The four-variable score for predicting cancer-free survival is calculated for a patient by adding the following numerical values: limited to the lung, zero, and extend-
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Table III. Correlation of predictive scores based upon the thirteen characteristics with observed outcome Patients used in deriving scoring Patients
used in testing scores
No. of
patients
Early experience
Total experience
Late experience
Early experience Late experience
304 362
Correlation 0.315* 0.174
Total
666
0.237
values
of score and 0.154 0.304*
outcome 0.275 0.268
0.235
0.270*
Legend: Early experience includes those patients operated upon in the period from September, 1957, to June 15, 1960. Late experience includes those operated upon in the period from June 16, 1960, to December, 1964. •Coefficients which resulted when the same patients were used to derive the scoring values and test the resultant scores.
Table IV. Correlation of predictive scores derived from the total patient experience with observed outcome Patients used in testing scores
Number of variables used in scoring patients Four*
Eight!
Thirteen
Score
No. of patients
Per cent
in test
Under 0.20 0.20-0.29 0.30-0.39 0.40-0.49 0.50 and over
115 231 230 101 90
54.8 39.8 26.5 23.8 12.2
Total
767
32.7
Number
of patients
Early experience Late experience
341 426
327 398
304 362
Total
767
725
666
Early experience Late experience Total
Correlation of score and outcome 0.309 0.299 0.275 0.235 0.263 0.268 0.268
0.278
Table V. Percentage of patients alive and cancer free by predictive scores based upon four variables and derived from the total patient experience
0.270
♦The four variables were tumor extending beyond the lung, age at randomization, involvement of mediastinal lymph nodes, and other pulmonary disease. fThe eight variables included the four variables plus blood vessel invasion, resection on the right side, physical evidence of cancer, and lymphatic invasion.
ing beyond the lung, 0.1675; age at randomization, age times 0.00353; mediastinal lymph nodes not involved, zero, and involved, 0.1389; other pulmonary disease not found, zero, and found, 0.1135. The score is designed so that an increase in score value signifies an increase in the probability that the disease will recur, or a decrease in the percentage of patients living and cancer free at 5 years (Table V ) . No score fell below 0.10 (the score of a 28year-old patient with no unfavorable indications), nor did any score exceed 0.68
(the score of a 74-year-old patient with tumor extending beyond the lung, with mediastinal nodes involved, and with another pulmonary disease). Percentages of patients alive and free of cancer at 5 years vary from 54.8 per cent in patients with scores less than 0.20 to 12.2 per cent for patients with scores of 0.50 or more. The effects of specific combinations of the predictive variables and the percentage of cancer-free survival are shown in Table VI. The most important factor from the standpoint of influence upon the 5 year cure rate is extension of the tumor beyond the lung, a finding which is associated with a decrease of 17 of the 5 year cures per 100 patients who have undergone resection. An age of 60 years or more appears to be a more important observation in patients with tumor that is confined to the lung. The effects of tumor in the mediastinal nodes
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Table VI. Percentage of patients alive and cancer free 5 years postoperatively for combinations of the four most predictive variables
Combination
Tumor limited to lung; age under 60 years
o f variable
Tumor limited to lung; age 60 years and over
Tumor Tumor beyond lung; beyond lung; age under age 60 years and over 60 years
Percentage alive and cancer free after 5 years* Mediastinal nodes not involved; no other pulmonary disease found Mediastinalnodes not involved; another pulmonary disease found Mediastinal nodes involved; no other pulmonary disease found Mediastinal nodes involved; another pulmonary disease found
51.9 (129)
39.5 (205)
28.6 (112)
24.6 (142)
47.1 (17)
34.1 (44)
0.0 (7)
13.8 (29)
14.3 (26)
24.1 (48)
33.3 (3)
0.0 (5)
'Figures in parentheses indicate numbers of patients in each group.
upon recurrence appears to vary, possibly due to small numbers; the average effect is a decrease of 14 cures per 100 patients. The presence of another pulmonary disease is associated with 11 fewer cures per 100 patients. Survival. Only patients who underwent operation prior to January, 1965, enabling them to be in the study at least 5 years as of January, 1970, were used in the analysis for the identification of factors predictive of outcome following a curative resection for lung cancer. However, the use of life-table procedures permitted all 1,803 patients with curative procedures through December, 1967, to be included in the study of postoperative survival. Postoperative survival curves have been computed for 752 patients with four-variable prognostic scores of less than 0.325 (more favorable), for 696 patients with scores of 0.325 or more (less favorable), and for the 355 patients whose scores were not computed because of incomplete information (Fig. 1). Patients with lower scores had a survival rate of 37 per cent at 5 years and 24 per cent at 10 years postoperatively, compared with 19 and 11 per cent, respectively, for patients with higher scores. The curve for patients with unknown scores, discontinued at 9 years postoperatively because too few patients were still
under observation, lies between the curves for patients with lower and higher scores but resembles the latter more closely. A question remains as to whether the mortality rate following a curative resection for lung cancer eventually returns to normal. One can estimate the number of deaths expected during each successive postoperative year by applying age-specific death rates for United States males to observed survivors. The relative risk of death, i.e., the number of deaths observed for each expected death, can then be used as a measure of the level of mortality following curative operation. The results have been summarized as average annual relative risks for remaining years of follow-up (Fig. 2 ) . The observed average annual death rate was 8.2 times expectation when computed from operation, declined to 1.9 times expectation for follow-up beyond the seventh postoperative year, and then increased with each succeeding year of follow-up, reaching 3.9 beyond 10 postoperative years. A similar analysis was repeated for highscore and low-score patients (Fig. 3). The average annual relative risk of death from operation was 9.8 for high-score patients compared to 6.4 for those with low scores, but both risks declined to 3 at 4 years after operation and remained about the same through 8 years postoperatively. Too few
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100 752 Patients with more fawrable scores 696 Patients with less favorable scores ■355 Patients without scores
8 9 10 3 4 5 6 7 Completed Postoperative Years Fig. 1. Per cent of survivors following curative surgery for bronchial carcinoma. Patients grouped by magnitude of four-variable score predictive of outcome relative to mean score.
0
1
2
rr
I
2
3
4
5
6
7
10
Completed Postoperative Years
P(RR«1)<.0001<0001<0001<.0001<.0001<.0001<.0001 .02 .02 .05 07 Fig. 2. Average annual relative risk of death during remainder of follow-up for patients with curative surgery for bronchial carcinoma. Expected mortality rate, based upon age-specific death rates for United States males and actual survivors at risk each year, equals unity. The area between 95 per cent confidence limits is shaded. RR, Relative risk.
patients have been followed beyond 8 years to attach any significance to the subsequent divergence of relative risks. Discussion In the present evaluation of the long-term survival of male patients with bronchial carcinoma who have undergone a curative resection, the major factor influencing such survival was the extent of the tumor at the
time of the resection. If the tumor was confined to the lung, long-term survival was a much greater possibility than if the tumor had spread to adjacent lymph nodes or to contiguous structures. A second but less important factor was the age of the patient; this had an adverse effect especially in patients with tumor confined to the lung who were 60 years of age or over. The presence of mediastinal node involvement and the
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Resection for bronchial carcinoma
10
9 8
\ \ \ \ \
397
752 Patients with more favorable scores "696 Patients with less favorable scores
7
6 to
Q
15
5 4 3
.5 0
♦Relative risks differ significantly P< .001. P > 05 for remaining comparisons.
1
2
3
4
5
6
7
8
9
10
Completed Postoperative Years RdffX.000K.0001
.0002
.18
.09
.91
.83
.84
.28
.69
Fig. 3. Average annual relative risk of death during remainder of follow-up by four-variable predictive score. Expected mortality rate equals unity.
presence of another pulmonary disease also adversely affected long-term survival. Actually, the derived four-variable predictive score was more efficient in predicting a treatment failure than in predicting longterm survival. This is readily understandable since, even with a grossly localized tumor, occult distant metastases may well be present. The failure of cell type and the size of the tumor to influence long-term survival in this series of patients remains somewhat difficult to explain. This is especially true since these factors did influence prognosis in the cases recently reported by Slack.2 In the series that he reported, the prognosis decreased with the increase in the tumor size. Also, the best prognosis was associated with the presence of a bronchiolar cell carcinoma and the poorest with an anaplastic tumor; in between these two extremes were the adenocarcinoma and the squamous cell tumors, for which the prognosis was about equal. However, it should be remembered that in regard to cell types, the two series are not comparable since, in the present Veterans Administration study, patients with bronchiolar cell carcinoma were excluded. Furthermore, women, who have a somewhat different incidence of the various
cell types than men have, likewise were excluded from the study. These two exclusions must be considered to have an effect on the relative significance of the influence of cell type in the present study. Furthermore, it should be noted that our usual understanding of the relationship of cell type to prognosis is based primarily upon the study of all patients with the disease. As a result, the entire clinical spectrum of the various lesions comes under consideration and, in this situation, the cell type of the tumor is of prognostic importance. On the other hand, the patients in the present series are highly selected; only those with lesions thought to have been totally removed at operation are included in the study. As a result, the significance of cell type may be lost readily in such a selected group of patients. It should be noted that patients with squamous cell carcinoma did fare somewhat better, as also reported by Higgins and Beebe.1 However, the finding was not statistically significant. As with the lack of significance of cell type, the lack of influence of tumor size may only reflect exclusion of the bronchiolar cell tumors or the inappropriate collection of relevant data from study of the operative specimen.
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Summary Patients in the Veterans Administration Surgical Adjuvant Cancer Chemotherapy trials who had curative resections, i.e., clinically no residual disease, during the first 10 years of study were evaluated for factors predictive of recurrence within 5 years of the operation. Thirteen characteristics which, in an earlier study, were found to be significantly associated with cancer-free survival 5 years postoperatively were reexamined in an effort to improve the ability to predict outcome on the basis of information available at operation. In order to restrict attention to failures due to the recurrence of disease, patients whose status for recurrence at 5 years postoperatively could not be determined were excluded from the analysis. The thirteen variables were examined for independent predictive information by means of stepwise multiple regression. Numerical values were assigned to each variable, with the sum for a patient being his predictive score. These derived scores were correlated with coded observed outcome (zero for success and one for failure) for a measure of association. The degree of association was greater—correlation coefficients (r) = 0.3—when the same group of patients used to derive the numerical values of observations was used to correlate computed scores with observed outcome; the degree of association was smallest but still statistically significant—r > 0.2—when a completely different group of patients was used to test the association of prediction and outcome. However, these associations are too low to permit accurate predictions for individual patients. The thirteen variables contain a substantial amount of shared predictive information. Restriction of prognostic scores to information carried by the eight or the four more important variables produced little, if any, reduction in the association of score with observed outcome. Predictions of outcome were equally good when based upon age of the patient and extension of the
Thoracic and Cardiovascular Surgery
tumor beyond the lung, involvement of mediastinal nodes, and the presence of another pulmonary disease. Four-variable scores defined categories of patients with prospects for 5 year cancer-free survival ranging from a high of 55 per cent to a low of 12 per cent. Four-variable scores were computed for 1,448 of the 1,803 patients with curative surgery in the study, and survival curves were computed. There were 752 patients whose scores were less than the mean score (0.325), thus more favorable, and 696 patients with scores equal to or greater than the mean, thus less favorable. In 355 patients, information was missing for one or more of the four variables, and thus a predictive score could not be computed. Survival rates in patients with the more favorable scores were 37 per cent at 5 years and 24 per cent at 10 years, compared with 19 and 11 per cent, respectively, in patients with less favorable scores. Survival rates in patients with unknown scores were slightly above those for patients with the less favorable scores. Average annual relative risks of death, i.e., the average number of observed deaths per remaining year of follow-up for each expected death, based upon age-specific death rates for the United States male population, was highest (8.2) at operation and lowest (1.9) beyond the seventh completed year of follow-up. The relative risk of death appeared to rise after 7 years of follow-up and significantly exceeded unity after 9 years. Too few patients were followed beyond the seventh postoperative year to conclude that the increase in relative risk was not due to chance. REFERENCES 1 Higgins, G. A., and Beebe, G. W.: Bronchogenic Carcinoma, Arch. Surg. 94: 539, 1967. 2 Slack, N. H.: Bronchogenic Carcinoma, Cancer 25: 987, 1970.
Appendix Principal investigators. George A. Higgins, Jr., Chairman, Washington, D. C ; Richard W. Dwight, Boston, Mass.; Philip Cooper, Bronx, N. Y.; Harry H. LeVeen, Brooklyn, N. Y.; Thomas W. Shields,
Volume 64 Number 3 September, 1972
Site Chairman, Chicago, 111.; Carl G. Schowengerdt, Cincinnati, Ohio; Jerry S. Wolkoff, Cleveland, Ohio; Robert Hays, Dallas, Texas; Oscar Serlin, East Orange, N. J.; William S. Walsh, Hines, 111.; Paul Jordan, Houston, Texas; Richard L. Lawton, Iowa City, Iowa; J. Harold Conn, Jackson, Miss.; Alfred Heilbrunn, Kansas City, Mo.; George L. Juler, Long Beach, Calif.; Edward W, Humphrey, Minneapolis, Minn.; James Yee, Martinez, Calif.; Stanley J. Dudrick, Philadelphia, Pa.; Adolph J. Yates, Pittsburgh, Pa.; Harold W. Harrower, Providence, R. I.; Jose H. Amadeo, San Juan, P. R.; Robert C. Donaldson, St. Louis, Mo.; Lloyd S. Rogers, Syracuse, N. Y.; Gale L. Mendeloff, Wood, Wis. Coordinator. Lyndon E. Lee, Jr., Associate Chief Medical Director for Professional Services, Department of Medicine and Surgery, Veterans Administration Central Office. Statistician. Robert J. Keehn, Follow-up Agency, National Academy of Sciences, National Research Council.
Discussion DR. R I C H A R D H. O V E R H O L T Boston,
Mass.
Dr. Shields and his co-authors have reduced the number of prediction factors for survival with cancer of the lung from thirteen down to four. In a retrospective study of close to 300 patients who have been cured in our series, we can find only three common denominators. First, all of these patients had an abnormal shadow on the x-ray film to lateralize the disease. Second, none of them had evidence of hematogenous dissemination. Third, almost all had been treated by surgical resection. It was the rare patient who had been treated by x-ray therapy alone and had survived 5 years. Curability seems to be in reverse proportion to the ease of histologic verification, other than surgical exploration. Chances for long-term survival are best when the lesion cannot be seen bronchoscopically, when bronchial secretions are negative for tumor cells, and when cervical and mediastinal nodes fail to settle the issue. [Slide] We reviewed 100 consecutive cases in which surgery indicated that the cancer apparently was localized. A fourth of these cases had been discovered by survey. Only 40 patients had preoperative histologic proof of cancer. Therefore, in 60 per cent of these most favorable situations, the issue was settled by a total biopsy which simultaneously provided the most promising therapy. It has been our hope that, as the years passed, more "silent" lesions would be discovered.
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[Slide] Dr. Francis Woods has recently reviewed our survey cases and has found that, up to 1955, only 4.2 per cent of all the cases were discovered by survey. However, in the last 10 years the incidence of survey among the total group has risen to 9 per cent, with an increase in resectability. As the authors have pointed out, the histologic type does not influence the survival rate exactly. However, the localization process has a greater importance at the time of incision. In our survey group, the number of undifferentiated lesions was only slightly less than the number of others. [Slide] Dr. Shields has stressed the importance of other factors in other pulmonary disease. It is ironic that the tars in inhaled cigarette smoke, which fertilize the cancer, also create chemical bronchitis and structural changes within the lung (emphysema) which remain after the operation. The smoke distribution and the damage is bilateral. The burden is not just at the portal of entry. Nicotine is in the smoke as well as tars. What this chronic poison has done to the circulatory system also relates to survival in the lung cancer patient. Therefore, we advise all patients of these multiple hazards, and we emphasize that pulmonary and circulatory function is so necessary to the duties as well as the pleasures of life that the crime of squandering it is equal to the folly. DR. T H O M A S W. S H I E L D S (Closing) I would like to thank Dr. Overholt for his remarks. In regard to cell type, there was a slight increase in survival in those patients who had squamous cell carcinoma over those who were classified in this particular study as having adenocarcinoma or undifferentiated cell types. However, the increase in survival was not statistically significant. I also might mention that the oat cell tumors were grouped into the undifferentiated category. This included a relatively small group of patients. In separating out the oat cell tumors, which were peripheral in location and only discovered at the time of frozen section analysis at operation, we found that 9.4 per cent of the patients who received Cytoxan postoperatively survived for 5 years, whereas only 3.8 per cent of the patients who received no other treatment survived that long. I believe that the significance of tumor size may well reflect the different locations of the various tumors (whether it was peripheral or whether it was central in location) as well as the effects of bronchial obstruction. As a result, tumor size per se is a difficult parameter to evaluate.