Refer to: Reynolds RD, Greenberg BR, Hill R, et al: Survival in lung cancer. West J Med 127:190-194, Sep 1977
Survival in Lung Cancer COL RALPH D. REYNOLDS, USAF, MC, Travis Air Force Base, California; BERNARD R. GREENBERG, MD, and RICHARD HILL, MD, Davis; COL RICHARD N. LUCAS, USAF, MC, and LT COL JAMES H. SHIRLEY, USAF, MC, Travis Air Force Base
Analysis was carried out according to stage and tissue type of 392 consecutive cases of lung cancer diagnosed at David Grant Medical Center between 1960 and 1974. Biphasic survival curves were described with a 'variable primary phase and a constant (1.1 percent per month) secondary phase. Survival was found to correlate both to histology and stage. The best survival was found in stage I bronchoalveolar carcinoma. Even in the more favorable categories a leveling off of survival was not found. This study strongly suggests that surgical treatment of lung cancer, while beneficial, cannot expect to be considered as a curative procedure in more than 10 percent of cases. Radiotherapy did not prolong survival. THE SURVIVAL in lung cancer is known to be dismal.3-8 Factors such as histologic type and extent of disease are recognized as being significant factors in the determination of survival.2'7 Most cases of lung cancer are unresectable at the time of diagnosis and fall into the category of stage III under the accepted classification by the American Joint Committee on Cancer Staging and End Results Reporting.2 The current study compares the survival in each of the histologic types and clinical stage. In addition, a fourth stage was devised to indicate those patients with extrathoracic metastasis at the time of diagnosis.
Methods Clinical records, tumor board files and histologic material of 403 consecutive cases of carcinoma of the lung diagnosed at David Grant Medical Center between 1960 and 1974 were reFrom the Hematology Oncology Service (Dr. Reynolds), Thoracic Surgery Service (Dr. Shirley), and the Department of Pathology (Dr. Lucas), David Grant Medical Center, Travis Air Force Base, California; and the Department of Medicine, University of California, Davis, School of Medicine (Drs. Greenberg and Hill). Submitted January 5, 1977. Reprint requests to: Col Ralph D. Reynolds, USAF, MC, Chief, Hematology Oncology Service (SGHMCO), David Grant Medical Center, Travis AFB, CA 94535.
190
SEPTEMBER 1977 * 127 * 3
viewed. Eleven were eliminated because of lack of histologic material for review or because of lack of followup data. The cases were analyzed according to the histologic type and classified in one of six groups: epidermoid, adenocarcinoma, undifferentiated small (oat) cell, anaplastic large cell, bronchoalveolar and nonclassifiable anaplastic carcinoma. Each histologic cell type was classified according to stage. In an attempt to separate the large number of those with stage III disease, an arbitrary division was made according to the presence or absence of extrathoracic disease at the time of diagnosis. Those with extrathoracic disease were classified as stage IV. Survival curves were calculated by the actuarial method; that is, the number living compared with the number at risk. When the survival curves for adenocarcinoma and epidermoid carcinoma were analyzed according to stage, a biphasic slope of the curve was noted. Estimates of the rates of death per month were then made based on the calculation of the slope of each curve. This was done in order to provide some degree of prognosis and predictability without waiting for completion of the end results reporting.
SURVIVAL IN LUNG CANCER
EPIDERMOID CARCINOMA STAGE I (27 -______ STAGE 11 (24) STAGE III (S2) - - - ---STAGE IV (26)
*********
....................
P60-
60
~
-*
so 40
40~ 30 20 10
140 30
1
3 4 5 6 78 910 YEARS FROM DIAGNOSIS Figure 1. Survival in 392 cases of lung cancer by stage. The slopes of all curves can be seen to have rapid primary and a constant secondary characteristic. 2
Results The number of cases with each histologic pattern and stage of disease is shown in Table 1. Epidermoid carcinoma was less likely to present with extrathoracic disease than adenocarcinoma or large cell carcinoma. Oat cell carcinoma and nonclassifiable undifferentiated carcinoma were more likely to present with advanced (stage III or IV) disease than the other tissue types. Bronchoalveolar was more likely to present as stage I disease. Squamous cell carcinoma was more likely to be resectable than adenocarinoma, large cell or oat cell carcinoma. Analysis of all patients (Figure 1) by stage, regardless of the cell type, showed a median survival of 38.2 months for stage I, 11.0 months for stage II, 7.3 months for stage III and 4.4 months for stage IV disease. After eight months the death rate was 1.1 percent per month in stage I cases. Before this period, the rate was 2.4 percent. For stage II disease, the initial death rate was 4.5 percent per month for 11 months and with a fall to 1.0 percent after 11 months. For
1
2
3
4
5
6 7 8910
YEARS FROM DIAGNOSIS Figure 2. Survival in 129 cases of epidermoid carcinoma of the lung by stage. The initial slope of the mortality curve varies by stage while the secondary stage is constant.
stage III, the rate was 7.0 percent per month for ten months and 1.1 thereafter. In stage IV, the primary death rate was 11.9 percent per month for seven months, falling to 1.0 percent after seven
months. It should be noted that the secondary death rates were almost identical regardless of the stage of disease. Analysis of epidermoid carcinoma survival by stage showed a distinct difference between each stage (Figure 2). Median survival for stage I was 33.9 months; for stage II, 21.3 months; for stage III, 8.2 months, and for stage IV, 3.2 months. The death rate was fairly constant in stage I disease after six months and was calculated to be 1.1 percent per month. The death rate for the first six months was 2.5 percent per month. The initial death rate had a greater impact on survival statistics with advancing stage. The death rate for the first six months in stage II disease was 5.5 percent per month and was 1.1 percent thereafter. The slope of the second portion of the survival curve was similar, therefore, to that
TABLE 1.-Numerical Listing of Cases of Lung Cancer by Stage and Histologic Type Squamous Cell AdenoCarcinoma
Stage I ..... Stage II ..... Stage III ..... Stage IV ..... Total .....
Oat Cell Large Cell
Bronchoalveolar
carcinoma Carcinoma Carcinoma Carcinoma
27 24 52 26
15 16 29 33
4 8 32 23
129
93
67
10 7 11 12 40.
16 4 6 3 29
Anaplastic NOC Carcinoma
3 0 11 20 34
Total
75 59 141 117 392
NOC =not otherwise classifiable
THE WESTERN JOURNAL OF MEDICINE
191
SURVIVAL IN LUNG CANCER
CD
=
1
3 4 5 6 7 8 910 2 YURS FROM DIAGNOSIS
Figure 3.-Survival in 122 cases of adenocarcinoma, including bronchoalveolar, by stage. A constant secondary mortality rate is again seen.
60
so60 30 z
32l°of a\ 'V 'S.V~~~~*.**
20-~ 10
'
1**
4 5 6 7 8 910 3 2 YEARS FROM DIAGNOSIS Figure 4. Survival in 93 cases of adenocarcinoma, excluding bronchoalveolar, by stage. 1
BRONCHOALVEOLAR
100 .
80 . X \ 70
60
STAGE I (16) STAGE 11( 4) .......................... STAGE III (6) - STAGE IV (3)
\
10"401
1
4 5 6 7 8 9 10 3 2 YEARS FROM DIAGNOSIS
Figure 5.-Survival in 29 cases of bronchoalveolar carcinoma by stage showing the poor survival in advanced disease.
192
SEPTEMBER 1977 * 127 * 3
found in stage I disease. Further analysis showed that this portion of the curve was similar for each stage of the disease. Survival therefore becomes an inverse factor of the slope and the duration of the initial portion of the survival curve. For stage III disease the initial mortality rate was six percent per month and for stage IV disease it was 12.5 percent per month. In each stage, the initial fall in survival was completed within ten months and the death rate then became similar regardless of stage. When adenocarcinoma and bronchoalveolar carcinoma were considered as a single group (Figure 3), the median survival for stage I was 32.2 months; for stage II, 21.5 months; for stage III, 8.9 months, and for stage IV, 4.7 months. The death rate in stage I disease was 1.1 percent per month. The mortality rate, for the first 24 months, in stage II adenocarcinoma was 2.5 percent per month. The rate then declined to 1.0 percent per month. The initial morality rate in stage III disease, as measured over the first 12 months, was 5.8 percent per month before declining to 1.1 percent per month. For stage IV disease, the death rate was 7.5 percent per month for the first 12 months before appearing to drop off to the lesser rate. Since the number of persons with stage III or IV disease surviving the initial death rate is small, the value of the second, or uniform, death rate is only important because of the comparison with lesser stages of disease. Analysis of the adenocarcinoma group, when bronchoalveolar cases have been excluded, is shown in Figure 4. The survival curves are less well defined than those seen in the previous groups. The median survival of stage I disease was 41.7 months; for stage II disease, 17.2 months; for stage III disease, 8.1 months, and for stage IV disease, 3.3 months. The calculated death rate was 1.2 percent per month in stage I adenocarcinoma. The initial death rate in stage II disease was 3.7 percent per month; for stage III disease, 5.5 percent, and for stage IV disease, 8.3 percent. Separate analysis of bronchoalveolar carcinoma, (Figure 5) showed a median survival for stage I disease to be 66 months while the median survival for stage II was 28.7 months; for stage III, 8.0 months, and for stage IV disease, it was 6.6 months. The median survival in large cell undifferentiated carcinoma was 20.5 months for stage I, 8.3 months for stage II, 5.2 months for stage III and 1.3 months for stage IV disease (Figure 6).
SURVIVAL IN LUNG CANCER
LARGE CELL CAKINOMA ******** STAGE I (10) STAGE 11 (7)
................ STAGE III (11) --STAGE IV (12)
70I i
RADIOTHERAPY: STAGE II EPDERMOID RADIOTHERAPY (9) ....... NO RADIOTHERAPY (10) 70
60.
60, 40'
s-
*
30 20. lo
**
50.I
40 30 20
10
..
0~~~~~~~~~
4 6 7 8 910 3 2 YEARS FROM DIAGNOSIS Figure 6.- Survival by stage in 40 cases of large cell carcinoma of the lung.
1
1
100
HISTOLOGK TYPE-ALL STAGES
%
90 t*\ .
...,.... I°v° RONCHOALVEOLAR (29)
so. \\ *
ADENOCARNOMA (124) EPSERMOID (129) 70 .\ **-----.-------- LAR EULL (40) --- eo ~ N.O.C. (34) ~~~ANAPLASTK -S..MAL (OAT) CELL (67) 0 4,
605 so
30 20
4000
0 z
10090RADIOTHERAPY: STAGE III EPIIDERMOID 80 ',\°LlESS THEN 450( O RADS (18) °°°°°°°°GREATER THAN 4500 RADS (16) 70- %\o%0 °o - NO RADIOTHERAkPY (4) 60. SO. I
Vtso
30-
0.*~
10
Figure 8.-Survival in stage 11 epidermoid carcinoma as influenced by radiotherapy. No beneficial effect on survival was found.
'I
\ \00 \
2 3 4 5 6 7 8 910 YEARS FROM DIAGNOSIS
......~~~~~~~~~~~~~~~
000
4 567 910O 2 3 YEARS FROM DIAGNOSIS Figure 7.-Survival in 392 cases of lung cancer by 1
201
w O.
_ot
10 II
|
ooo
r*
i.. Z.--
--
Ai
I
I
A
I
3 2 4 S 6 7 8 910 YEARS FROM DIAGNOSIS Figure 9.-Survival in 38 cases of stage III epidermoid carcinoma according to radiation dose. No beneficial
1
histologic types. The median survival exceeded 12 months in only bronchoalveolar carcinoma, a reflection of the predominance of stages I and 11 disease in thisdisorder.
effect on survival could be shown.
The median survival for both stage I and II oat cell carcinoma was 7.4 months. With a total of only 12 cases in this combined category, no difference could be found between the two stages. The median survival in stages III and IV also failed to show any separation (7.4 months). Evaluation by histology without regard to stage (Figure 7) fails to show clear divisions in the slopes of the survival curves. While survival in bronchoalveolar carcinoma is superior to the other histologic categories, this advantage was less pronounced than was anticipated before this study. The survival curve suggests that the improved survival is related to early detection with regard to clinical stage rather than to a relatively benign nature of the disease process. The high propor-
tion of stage I disease mentioned earlier is probably a manifestation of the more common peripheral location and slow doubling time in this tumor type. The median survival of the bronchoalveolar carcinoma cases in this series was only 18.0 months. By comparison, the median survival in adenocarcinoma, large cell, epidermoid, oat cell and anaplastic not otherwise classifiable (NOC) carcinomas was 11.0, 9.9, 8.5, 7.4 and 4.5 months respectively. Both stage II and stage III cases of epidermoid carcinoma were evaluated for the effects of postoperative radiation therapy (Figure 8). In stage II disease, nine patients received radiation therapy and ten did not. The survival curve in this group of patients showed no advantage for using postTHE WESTERN JOURNAL OF MEDICINE
193
SURVIVAL IN LUNG CANCER
operative radiotherapy. The median survival in the radiation treated group was 23.5 months and in the untreated group 30.7 months. It should be noted that there was no clear separation between the two groups. All patients in the untreated group had died at 48 months while two patients in the treated group lived beyond 48 months. The cases of epidermoid carcinoma with stage lII disease (Figure 9) were divisable into three groups: those who received no radiotherapy, those who received less than 4,500 rads to the involved field and those who received more than 4,500 rads. The median survival was calculated as 7.5 months in the untreated group, 8.5 months in the minimum treated group and 7.5 months in the full treatment group.
Discussion This analysis of 392 consecutive cases of lung cancer diagnosed at a single institution gives a clear picture of the rapidly fatal nature of this disease. The breakdown of the classification into stages III and IV disease seems reasonable and is supported by the survival statistics in each of the histologic subtypes. Comparison with reports in the literature shows that both the distribution of cases and survival are similar.1'3"'6-8 The biphasic nature of the survival curves has not been previously described. Discrepancies between survival in other reports4 are felt to be attributable to the methods of reporting and the superiority of the maintenance of the institutional tumor registry as compared with large scale central registration of data. The negative value of postoperative radiation therapy has been previously described.5 The separation of each histologic type by stage has shown that the death rate may be described in two phases. The first, or primary phase, assumes the characteristic of the type and stage of the tumor. It was found to have increasing value with more advanced disease. On the other hand, the secondary death rate was found to be constant. The death rate during this secondary phase was found to be 1.1 percent per month in nearly all stages of these histologic categories. The median survival was found to be related both to histologic type and to clinical stage. More meaningful data were obtained when both were analyzed together. The best median survival was found in stage I bronchoalveolar carcinoma (66 months). Stage I adenocarcinoma had a median survival of 41.7 months while epidermoid car194
SEPTEMBER 1977 *
127 * 3
cinoma was 33.9 months. The best median survival in stage II disease was also found in the bronchoalveolar group (28.7 months), while adenocarcinoma and epidermoid carcinoma had median survivals of 17.2 and 21.3 months, respectively. The median survival in stage III disease was 8.2 months for epidermoid, 8.1 months for adenocarcinoma and 8.0 months for bronchoalveolar carcinoma. The median survival in stage IV disease was 6.6 months for bronchoalveolar carcinoma, 3.3 months for adenocarcinoma and 3.2 months for epidermoid carcinoma. Therefore, there appears to be a clear distinction between stages III and IV as determined by the extrathoracic metastsis. Mountain7 previously described the difference in survival between those without distant metastasis (M0) and those with distant metastasis (M1), but did not make the differentiation within the advanced stages of lung cancer. Oat cell carcinoma in this series was found to have a uniformly poor median survival (7.4 months) regardless of the stage at the time of presentation. These data suggest that oat cell carcinoma is frequently a systemic disease with metastasis commonly present at the time of diagnosis. Analysis of those resected for cure (stages I and II) suggests that in few, if any, of the patients is surgical cure achieved. Though early detection and surgical resection remain both the treatment of choice and the most important factors in prolonging survival, it appears clear that in 10 percent or less can permanent cure by the surgical procedure be expected, even in the most favorable circumstances. Deaths continue to occur well beyond the five-year period postoperatively. More effective combined modality management of lung cancer is urgently needed. REFERENCES 1. Berge T, Toremalm NG: Bronchial cancer-A clinical and pathological study. Scand J Resp Dis 56:109-119, 1975 2. Carr DT: A Report on the Development of the Staging System for Cancer of the Lung-Sixth National Cancer Conference Proceedings. Philadelphia, J B Lippincott Company, 1970, pp 877-878 3. Green N, Kurohara SS, George FW: Cancer of the lung. Cancer 25:1229-1233, 1971 4. Katsuki H, Shimada K, Koyama A, et al: Long-term adjuvant chemotherapy for primary, resected lung cancer. J Thorac Cardiovasc Surg 70:590-605, 1975 5. Krant MJ: The question of irradiation therapy in lung cancer. JAMA 195:471-475, 1966 6. Lince L. Lulu DJ: Carcinoma of the lung. Arch Surg 102: 103-107, 1971 7. Mountain CF, Carr DT, Anderson WAD: A system for the clinical staging of lung cancer. Am J Roentgenol Radium Ther Nucl Med 120:130-138, 1974 8. Weiss W: Survivorship among men with bronchogenic carcinoma. Arch Environ Health 22:168-173, 1971
Survival in Lung Cancer COL RALPH D. REYNOLDS, USAF, MC, Travis Air Force Base, California; BERNARD R. GREENBERG, MD, and RICHARD HILL, MD, Davis; COL RICHARD N. LUCAS, USAF, MC, and LT COL JAMES H. SHIRLEY, USAF, MC, Travis Air Force Base
Analysis was carried out according to stage and tissue type of 392 consecutive cases of lung cancer diagnosed at David Grant Medical Center between 1960 and 1974. Biphasic survival curves were described with a 'variable primary phase and a constant (1.1 percent per month) secondary phase. Survival was found to correlate both to histology and stage. The best survival was found in stage I bronchoalveolar carcinoma. Even in the more favorable categories a leveling off of survival was not found. This study strongly suggests that surgical treatment of lung cancer, while beneficial, cannot expect to be considered as a curative procedure in more than 10 percent of cases. Radiotherapy did not prolong survival. THE SURVIVAL in lung cancer is known to be dismal.3-8 Factors such as histologic type and extent of disease are recognized as being significant factors in the determination of survival.2'7 Most cases of lung cancer are unresectable at the time of diagnosis and fall into the category of stage III under the accepted classification by the American Joint Committee on Cancer Staging and End Results Reporting.2 The current study compares the survival in each of the histologic types and clinical stage. In addition, a fourth stage was devised to indicate those patients with extrathoracic metastasis at the time of diagnosis.
Methods Clinical records, tumor board files and histologic material of 403 consecutive cases of carcinoma of the lung diagnosed at David Grant Medical Center between 1960 and 1974 were reFrom the Hematology Oncology Service (Dr. Reynolds), Thoracic Surgery Service (Dr. Shirley), and the Department of Pathology (Dr. Lucas), David Grant Medical Center, Travis Air Force Base, California; and the Department of Medicine, University of California, Davis, School of Medicine (Drs. Greenberg and Hill). Submitted January 5, 1977. Reprint requests to: Col Ralph D. Reynolds, USAF, MC, Chief, Hematology Oncology Service (SGHMCO), David Grant Medical Center, Travis AFB, CA 94535.
190
SEPTEMBER 1977 * 127 * 3
viewed. Eleven were eliminated because of lack of histologic material for review or because of lack of followup data. The cases were analyzed according to the histologic type and classified in one of six groups: epidermoid, adenocarcinoma, undifferentiated small (oat) cell, anaplastic large cell, bronchoalveolar and nonclassifiable anaplastic carcinoma. Each histologic cell type was classified according to stage. In an attempt to separate the large number of those with stage III disease, an arbitrary division was made according to the presence or absence of extrathoracic disease at the time of diagnosis. Those with extrathoracic disease were classified as stage IV. Survival curves were calculated by the actuarial method; that is, the number living compared with the number at risk. When the survival curves for adenocarcinoma and epidermoid carcinoma were analyzed according to stage, a biphasic slope of the curve was noted. Estimates of the rates of death per month were then made based on the calculation of the slope of each curve. This was done in order to provide some degree of prognosis and predictability without waiting for completion of the end results reporting.
SURVIVAL IN LUNG CANCER
EPIDERMOID CARCINOMA STAGE I (27 -______ STAGE 11 (24) STAGE III (S2) - - - ---STAGE IV (26)
*********
....................
P60-
60
~
-*
so 40
40~ 30 20 10
140 30
1
3 4 5 6 78 910 YEARS FROM DIAGNOSIS Figure 1. Survival in 392 cases of lung cancer by stage. The slopes of all curves can be seen to have rapid primary and a constant secondary characteristic. 2
Results The number of cases with each histologic pattern and stage of disease is shown in Table 1. Epidermoid carcinoma was less likely to present with extrathoracic disease than adenocarcinoma or large cell carcinoma. Oat cell carcinoma and nonclassifiable undifferentiated carcinoma were more likely to present with advanced (stage III or IV) disease than the other tissue types. Bronchoalveolar was more likely to present as stage I disease. Squamous cell carcinoma was more likely to be resectable than adenocarinoma, large cell or oat cell carcinoma. Analysis of all patients (Figure 1) by stage, regardless of the cell type, showed a median survival of 38.2 months for stage I, 11.0 months for stage II, 7.3 months for stage III and 4.4 months for stage IV disease. After eight months the death rate was 1.1 percent per month in stage I cases. Before this period, the rate was 2.4 percent. For stage II disease, the initial death rate was 4.5 percent per month for 11 months and with a fall to 1.0 percent after 11 months. For
1
2
3
4
5
6 7 8910
YEARS FROM DIAGNOSIS Figure 2. Survival in 129 cases of epidermoid carcinoma of the lung by stage. The initial slope of the mortality curve varies by stage while the secondary stage is constant.
stage III, the rate was 7.0 percent per month for ten months and 1.1 thereafter. In stage IV, the primary death rate was 11.9 percent per month for seven months, falling to 1.0 percent after seven
months. It should be noted that the secondary death rates were almost identical regardless of the stage of disease. Analysis of epidermoid carcinoma survival by stage showed a distinct difference between each stage (Figure 2). Median survival for stage I was 33.9 months; for stage II, 21.3 months; for stage III, 8.2 months, and for stage IV, 3.2 months. The death rate was fairly constant in stage I disease after six months and was calculated to be 1.1 percent per month. The death rate for the first six months was 2.5 percent per month. The initial death rate had a greater impact on survival statistics with advancing stage. The death rate for the first six months in stage II disease was 5.5 percent per month and was 1.1 percent thereafter. The slope of the second portion of the survival curve was similar, therefore, to that
TABLE 1.-Numerical Listing of Cases of Lung Cancer by Stage and Histologic Type Squamous Cell AdenoCarcinoma
Stage I ..... Stage II ..... Stage III ..... Stage IV ..... Total .....
Oat Cell Large Cell
Bronchoalveolar
carcinoma Carcinoma Carcinoma Carcinoma
27 24 52 26
15 16 29 33
4 8 32 23
129
93
67
10 7 11 12 40.
16 4 6 3 29
Anaplastic NOC Carcinoma
3 0 11 20 34
Total
75 59 141 117 392
NOC =not otherwise classifiable
THE WESTERN JOURNAL OF MEDICINE
191
SURVIVAL IN LUNG CANCER
CD
=
1
3 4 5 6 7 8 910 2 YURS FROM DIAGNOSIS
Figure 3.-Survival in 122 cases of adenocarcinoma, including bronchoalveolar, by stage. A constant secondary mortality rate is again seen.
60
so60 30 z
32l°of a\ 'V 'S.V~~~~*.**
20-~ 10
'
1**
4 5 6 7 8 910 3 2 YEARS FROM DIAGNOSIS Figure 4. Survival in 93 cases of adenocarcinoma, excluding bronchoalveolar, by stage. 1
BRONCHOALVEOLAR
100 .
80 . X \ 70
60
STAGE I (16) STAGE 11( 4) .......................... STAGE III (6) - STAGE IV (3)
\
10"401
1
4 5 6 7 8 9 10 3 2 YEARS FROM DIAGNOSIS
Figure 5.-Survival in 29 cases of bronchoalveolar carcinoma by stage showing the poor survival in advanced disease.
192
SEPTEMBER 1977 * 127 * 3
found in stage I disease. Further analysis showed that this portion of the curve was similar for each stage of the disease. Survival therefore becomes an inverse factor of the slope and the duration of the initial portion of the survival curve. For stage III disease the initial mortality rate was six percent per month and for stage IV disease it was 12.5 percent per month. In each stage, the initial fall in survival was completed within ten months and the death rate then became similar regardless of stage. When adenocarcinoma and bronchoalveolar carcinoma were considered as a single group (Figure 3), the median survival for stage I was 32.2 months; for stage II, 21.5 months; for stage III, 8.9 months, and for stage IV, 4.7 months. The death rate in stage I disease was 1.1 percent per month. The mortality rate, for the first 24 months, in stage II adenocarcinoma was 2.5 percent per month. The rate then declined to 1.0 percent per month. The initial morality rate in stage III disease, as measured over the first 12 months, was 5.8 percent per month before declining to 1.1 percent per month. For stage IV disease, the death rate was 7.5 percent per month for the first 12 months before appearing to drop off to the lesser rate. Since the number of persons with stage III or IV disease surviving the initial death rate is small, the value of the second, or uniform, death rate is only important because of the comparison with lesser stages of disease. Analysis of the adenocarcinoma group, when bronchoalveolar cases have been excluded, is shown in Figure 4. The survival curves are less well defined than those seen in the previous groups. The median survival of stage I disease was 41.7 months; for stage II disease, 17.2 months; for stage III disease, 8.1 months, and for stage IV disease, 3.3 months. The calculated death rate was 1.2 percent per month in stage I adenocarcinoma. The initial death rate in stage II disease was 3.7 percent per month; for stage III disease, 5.5 percent, and for stage IV disease, 8.3 percent. Separate analysis of bronchoalveolar carcinoma, (Figure 5) showed a median survival for stage I disease to be 66 months while the median survival for stage II was 28.7 months; for stage III, 8.0 months, and for stage IV disease, it was 6.6 months. The median survival in large cell undifferentiated carcinoma was 20.5 months for stage I, 8.3 months for stage II, 5.2 months for stage III and 1.3 months for stage IV disease (Figure 6).
SURVIVAL IN LUNG CANCER
LARGE CELL CAKINOMA ******** STAGE I (10) STAGE 11 (7)
................ STAGE III (11) --STAGE IV (12)
70I i
RADIOTHERAPY: STAGE II EPDERMOID RADIOTHERAPY (9) ....... NO RADIOTHERAPY (10) 70
60.
60, 40'
s-
*
30 20. lo
**
50.I
40 30 20
10
..
0~~~~~~~~~
4 6 7 8 910 3 2 YEARS FROM DIAGNOSIS Figure 6.- Survival by stage in 40 cases of large cell carcinoma of the lung.
1
1
100
HISTOLOGK TYPE-ALL STAGES
%
90 t*\ .
...,.... I°v° RONCHOALVEOLAR (29)
so. \\ *
ADENOCARNOMA (124) EPSERMOID (129) 70 .\ **-----.-------- LAR EULL (40) --- eo ~ N.O.C. (34) ~~~ANAPLASTK -S..MAL (OAT) CELL (67) 0 4,
605 so
30 20
4000
0 z
10090RADIOTHERAPY: STAGE III EPIIDERMOID 80 ',\°LlESS THEN 450( O RADS (18) °°°°°°°°GREATER THAN 4500 RADS (16) 70- %\o%0 °o - NO RADIOTHERAkPY (4) 60. SO. I
Vtso
30-
0.*~
10
Figure 8.-Survival in stage 11 epidermoid carcinoma as influenced by radiotherapy. No beneficial effect on survival was found.
'I
\ \00 \
2 3 4 5 6 7 8 910 YEARS FROM DIAGNOSIS
......~~~~~~~~~~~~~~~
000
4 567 910O 2 3 YEARS FROM DIAGNOSIS Figure 7.-Survival in 392 cases of lung cancer by 1
201
w O.
_ot
10 II
|
ooo
r*
i.. Z.--
--
Ai
I
I
A
I
3 2 4 S 6 7 8 910 YEARS FROM DIAGNOSIS Figure 9.-Survival in 38 cases of stage III epidermoid carcinoma according to radiation dose. No beneficial
1
histologic types. The median survival exceeded 12 months in only bronchoalveolar carcinoma, a reflection of the predominance of stages I and 11 disease in thisdisorder.
effect on survival could be shown.
The median survival for both stage I and II oat cell carcinoma was 7.4 months. With a total of only 12 cases in this combined category, no difference could be found between the two stages. The median survival in stages III and IV also failed to show any separation (7.4 months). Evaluation by histology without regard to stage (Figure 7) fails to show clear divisions in the slopes of the survival curves. While survival in bronchoalveolar carcinoma is superior to the other histologic categories, this advantage was less pronounced than was anticipated before this study. The survival curve suggests that the improved survival is related to early detection with regard to clinical stage rather than to a relatively benign nature of the disease process. The high propor-
tion of stage I disease mentioned earlier is probably a manifestation of the more common peripheral location and slow doubling time in this tumor type. The median survival of the bronchoalveolar carcinoma cases in this series was only 18.0 months. By comparison, the median survival in adenocarcinoma, large cell, epidermoid, oat cell and anaplastic not otherwise classifiable (NOC) carcinomas was 11.0, 9.9, 8.5, 7.4 and 4.5 months respectively. Both stage II and stage III cases of epidermoid carcinoma were evaluated for the effects of postoperative radiation therapy (Figure 8). In stage II disease, nine patients received radiation therapy and ten did not. The survival curve in this group of patients showed no advantage for using postTHE WESTERN JOURNAL OF MEDICINE
193
SURVIVAL IN LUNG CANCER
operative radiotherapy. The median survival in the radiation treated group was 23.5 months and in the untreated group 30.7 months. It should be noted that there was no clear separation between the two groups. All patients in the untreated group had died at 48 months while two patients in the treated group lived beyond 48 months. The cases of epidermoid carcinoma with stage lII disease (Figure 9) were divisable into three groups: those who received no radiotherapy, those who received less than 4,500 rads to the involved field and those who received more than 4,500 rads. The median survival was calculated as 7.5 months in the untreated group, 8.5 months in the minimum treated group and 7.5 months in the full treatment group.
Discussion This analysis of 392 consecutive cases of lung cancer diagnosed at a single institution gives a clear picture of the rapidly fatal nature of this disease. The breakdown of the classification into stages III and IV disease seems reasonable and is supported by the survival statistics in each of the histologic subtypes. Comparison with reports in the literature shows that both the distribution of cases and survival are similar.1'3"'6-8 The biphasic nature of the survival curves has not been previously described. Discrepancies between survival in other reports4 are felt to be attributable to the methods of reporting and the superiority of the maintenance of the institutional tumor registry as compared with large scale central registration of data. The negative value of postoperative radiation therapy has been previously described.5 The separation of each histologic type by stage has shown that the death rate may be described in two phases. The first, or primary phase, assumes the characteristic of the type and stage of the tumor. It was found to have increasing value with more advanced disease. On the other hand, the secondary death rate was found to be constant. The death rate during this secondary phase was found to be 1.1 percent per month in nearly all stages of these histologic categories. The median survival was found to be related both to histologic type and to clinical stage. More meaningful data were obtained when both were analyzed together. The best median survival was found in stage I bronchoalveolar carcinoma (66 months). Stage I adenocarcinoma had a median survival of 41.7 months while epidermoid car194
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cinoma was 33.9 months. The best median survival in stage II disease was also found in the bronchoalveolar group (28.7 months), while adenocarcinoma and epidermoid carcinoma had median survivals of 17.2 and 21.3 months, respectively. The median survival in stage III disease was 8.2 months for epidermoid, 8.1 months for adenocarcinoma and 8.0 months for bronchoalveolar carcinoma. The median survival in stage IV disease was 6.6 months for bronchoalveolar carcinoma, 3.3 months for adenocarcinoma and 3.2 months for epidermoid carcinoma. Therefore, there appears to be a clear distinction between stages III and IV as determined by the extrathoracic metastsis. Mountain7 previously described the difference in survival between those without distant metastasis (M0) and those with distant metastasis (M1), but did not make the differentiation within the advanced stages of lung cancer. Oat cell carcinoma in this series was found to have a uniformly poor median survival (7.4 months) regardless of the stage at the time of presentation. These data suggest that oat cell carcinoma is frequently a systemic disease with metastasis commonly present at the time of diagnosis. Analysis of those resected for cure (stages I and II) suggests that in few, if any, of the patients is surgical cure achieved. Though early detection and surgical resection remain both the treatment of choice and the most important factors in prolonging survival, it appears clear that in 10 percent or less can permanent cure by the surgical procedure be expected, even in the most favorable circumstances. Deaths continue to occur well beyond the five-year period postoperatively. More effective combined modality management of lung cancer is urgently needed. REFERENCES 1. Berge T, Toremalm NG: Bronchial cancer-A clinical and pathological study. Scand J Resp Dis 56:109-119, 1975 2. Carr DT: A Report on the Development of the Staging System for Cancer of the Lung-Sixth National Cancer Conference Proceedings. Philadelphia, J B Lippincott Company, 1970, pp 877-878 3. Green N, Kurohara SS, George FW: Cancer of the lung. Cancer 25:1229-1233, 1971 4. Katsuki H, Shimada K, Koyama A, et al: Long-term adjuvant chemotherapy for primary, resected lung cancer. J Thorac Cardiovasc Surg 70:590-605, 1975 5. Krant MJ: The question of irradiation therapy in lung cancer. JAMA 195:471-475, 1966 6. Lince L. Lulu DJ: Carcinoma of the lung. Arch Surg 102: 103-107, 1971 7. Mountain CF, Carr DT, Anderson WAD: A system for the clinical staging of lung cancer. Am J Roentgenol Radium Ther Nucl Med 120:130-138, 1974 8. Weiss W: Survivorship among men with bronchogenic carcinoma. Arch Environ Health 22:168-173, 1971
