Cancer of the bronchus and lung: Connecticut 1935–1959

J. chron. Dis. 1964, Vol. 17, pp. 1033-1054. Pergamon Press Ltd. Printed in Great Britain

CANCER

OF THE BRONCHUS CONNECTICUT

HENRY EISENBERG, M.D.,

M.P.H.?,

AND LUNG:

1935-1959*

JAY M. SHAMES, M.D.$,

WESLEY L. HOLLOWAY,

B.A.7 and HAROLD S. BARRETT, M.D., M.P.H.? Chronic Disease Control Section, Connecticut State Department of Health, Hartford, Conn. (Received

14 February

1964)

THIS

is a report on patients diagnosed with cancer of the bronchus and lung in Connecticut hospitals during the 25-year period, 1935-1959. Previous studies have been conducted on cancer of the breast [l], uterus [2], ovary [3], stomach [4], and large intestine and rectum [5]. The data are based on information routinely submitted by 36 hospitals to the tumor registry operated by the Connecticut State Department of Health, the history of which has been described by GRISWOLD and CUTLER [6] and GREENBERG [7]. An electronic computer available at the National Institutes of Health made this analysis possible. The data from the Connecticut Registry are unique in that they provide information on virtually all known cases of cancer in a community, rather than on patients admitted to an individual treatment center. Whereas patients seen at an individual treatment center may be selected with respect to socio-economic status, stage of disease, or general clinical conditions, the data in this report describe the survival experience of unselected patients with cancer of the lung. METHODOLOGY

In this study, the actuarial method was used in analyzing survival. An important advantage of this method for analyzing survival is that it makes possible the use of all survival information accumulated up to the closing date of the study. In calculating a 5-year survival rate, computations need not be restricted to patients diagnosed more than 5 years prior to the closing date of the study; in calculating a IO-year survival rate, computations need not be restricted to patients diagnosed more than 10 years prior to the closing date of the study. Thus, all information accumulated through 31st December 1956, was used in analyzing survival experience among patients during the period, 1935 through 1956. Under this procedure, the effective number of patients contributing information to the calculated survival rate declines with survival time. The effective number is the number of patients in a sample in which all members would be followed to death or to the end of the specified period of observation and which would yield a survival rate and a standard error equal to the values observed. For *Supported by Grant No. CA 09808-04, National Institute of Health. TChief, Chronic Disease Control Section, Connecticut State Department of Health; Research Statistician, Chronic Disease Control Section, Connecticut State Department of Health; and Deputy Commissioner of Health, Connecticut State Department of Health, respectively. JPublic Health Service Officer, assigned to Connecticut State Department of Health, Chronic Disease Control Section. 1033

1034

HENRY EISENBERG,JAY M. SHAMES, WESLEY L. HOLLOWAY and HAROLD S. BARRETI

example, the effective number of patients that contributed information to the calculated IO-year survival rate was smaller than the effective number that contributed information to the calculated 5-year survival rate. The statistical reliability of the calculated survival rate is, of course, dependent on the effective number. This is reflected in the standard error of the survival rate, which provides a measure of the extent to which the computed rate may have been influenced by sampling variation. For example, by adding twice the standard error to and subtracting it from the computed survival rate, an approximate 95 per cent confidence interval is obtained. This means that in repeated observations under the same conditions the true survival rate will be within a range of two standard errors on either side of the computed rate, an average of 95 times in 100. The standard error of the survival rate has been computed by a method developed by GREENWOOD [8]. Connecticut life tables for 1940 and 1950 were used in estimating expected survival rates based on general population experience. Values for intermediate years were obtained by straight line interpolation. Connecticut life-table values for 1955 were estimated by applying the observed ratio of Connecticut to United States life-table values for 1950, to the United States life table for 1955. Expected survival rates for 1951 through 1954, were obtained by interpolation. Two factors were taken into account in calculating the expected survival rates for each follow-up year: (1) the age distribution of the patient population at the beginning of each year, and (2) the secular trend in life-table values for the general population between 1940 and 1955. In this analysis, the patient population was divided into two cohorts with respect to the calendar period of diagnosis; 1935-1949 and 1950-1956. The selection of unequal spans of time for the two groups is necessary in order to get relatively similar numbers of cases in each period. Each cohort was subdivided into five age groups: under 45,45-54, 55-64,65-74, and 75 and over. In estimating expected survival rates from the Connecticut life tables, all members of a cohort were treated as having had a diagnosis at the midpoint of the calendar period of diagnosis; the midpoint of each age group was used to characterize all its members. For age groups under 45 and 75 and over, we arbitrarily assumed midpoints of 40 years and 80 years. For example, for patients whose disease was diagnosed during the period, 1935-1949, and who were 4554 years of age at that time, the expected survival rates for the first follow-up year were based on age 50 in the 1940 life tables, for the second year they were based on age 51 in the 1941 life table, for the third year on age 52 in the 1942 life table, and so on. In addition to subdivision by period of diagnosis, age, sex, and primary site, patient population was further subclassified with respect to extent of disease at diagnosis (stage), method of treatment during the first course of therapy, and histological type. Figures are presented on the incidence and survival rates of patients with cancer of the bronchus and lung in Connecticut. The records upon which the age-adjusted incidence rates are based include all cases diagnosed as bronchogenic cancer for a given year between 1935-1959. Cases without hospitalization or microscopic confirmation and death certificate only reports are included in the incidence data. The survival information has been obtained from the Connecticut Tumor Registry. These cases were diagnosed at time of hospital admission during the time period of 1935-1956, and were followed during the course of their illness. All of the cases included in the survival data have been microscopically confirmed.

Cancer of the Bronchus and Lung: Connecticut

1935-1959

1035

RESULTS

Incidence

The incidence of cancer of the bronchus and lung for males and females of all ages in Connecticut has risen dramatically, from 1935 to 1959. The rate per 100,000 for males rose from 8.7 in 1935 to a rate of 46.7 in 1959-a 436.8 per cent increase The comparable rise of this disease in females was from 4.1 per 100,000 in 1935 to 7.3 in 1959. The number of cases reported in this time period was 6610 males and 1285 females. The change in incidence rates, from 1935 to 1959, is shown in Figs. 1 and 2. A much higher incidence can be noted in Fig. 2, in which the population studied is limited to the age group, 45-64. 100 90 80 -~70-

2

I

I

Trend

----

“]‘,I

!

‘!1936 '38!,!‘I’,'40

'42

'44

'45

'40

'5C

'52

'54

'56

'58

Years FIG. 1. Age-adjusted incidence per 100,000 population of cancer of the bronchus and lung among males and females, all ages. Cases diagnosed in Connecticut, 1935-59.

Survival

For purposes of analyzing survival, information is presented for 2766 microscopically confirmed cases of cancer of the bronchus and lung-2353 men and 413 women. Since the population of Connecticut contains less than 3percent non-whites, no distinction of race has been made. To provide a basis for evaluating changes over time, the patients are divided into two groups according to calendar periods of diagnosis; It can be noted there are 1935-1949 (1135 patients) and 1950-1956 (1631 patients). significantly more patients in the last 7-year period than in the entire preceding 15year interval. The male-female ratio in the 1935-1949 period was 4.6 : 1 as opposed to 6.7 : 1 in the 1950-1956 period. This increase in number of cases has been reported by other authors [g-12]. The sex ratio reported is similar to that noted by BOYD at the

HENRYEJSENBERG, JAYM. SHAMES,WESLEYL. HOLLOWAYand HAROLDS. BARRETT

1036

,40tIZO--IOOgo--80--

70--60-50--

40-

?? 2 20--

Ci

E 2

3

r

I

Trend

----

,’

I/l!l!/:‘!‘! 1936 '38 '40

‘!I’

:

'42

'46

'44

V!‘!‘!‘!‘!’ '50 '52

'48

1

~

'54

'56

'58

Yeors

FIG. 2. Age-adjusted incidence per 100,000 population of cancer of the bronchus and lung among males and females, ages 45-64. Cases diagnosed in Connecticut, 1935-59.

Lahey Clinic [13-141, but differs considerably from the 8-10 : 1 reported by other authors [15-191. The age and sex distribution of the patients with cancer of the lung is shown in Table 1. It can be seen that the majority of patients are between 45 and 75 years old with the average being between 57 and 61 years of age. It should be noted that there is TABLET.

PERCENTAOEAGEDISTRIEUTIONBYSEXANDCALENDARPERIODOFDIAGNOSIS. CANCEROFTHEBRONCHUSAND LUNG DIAGNOSEDIN CONNECTICU'T

Both sexes

___.

193549

PATIIZNTSWITH

1935-56

Male

-

Female

1950-56

193549

1950-56

193549

1950-56

Number of cases

1135

1631

933

1420

202

211

% distribution All ages* Under 45 45-54 554 65-74 75 and over

100 12 26 38 19 5

100 6 22 38 28 6

100 9 27 41 19 4

100 5 21 40 29 5

100 21 23 28 18 10

100 13 23 27 26 10

Median age Average age *Percentages

58.2 57.9

60.8 60.5

may not total 100 because of rounding.

56.8 58.1

60.9 60.7

57.1 56.9

60.0 59.5

Cancer of the Bronchus and Lung: Connecticut

1037

19351959

a greater clustering of males around the average age and a wider age distribution for females. It appears that females get lung cancer at an earlier age than males. The age distribution found is similar to that of most other authors. Table 2 summarizes a follow-up of information of the 2766 patients with cancer of the lung. Only 18 (0.7 per cent) of the patients were lost to follow-up during the first 5 years. Because of the small number of patients surviving 5 years, the observed survival rates for those surviving longer than 5 years are not statistically reliable. TABLET. FOLLOW-~PSTATIJSOFPAT~TS~~~CANCEROFTHEBRON~HUSAND LUNGDIAGNOSED IN ChNECTICIJT 1935-56, BY ~-MONTH AND S-YEAR FOLLOW-up INTERVALS, AND CALENDAR PERIOD OF DIAGNOSIS

Calender period of diagnosis and follow-up interval

Lost to follow-up during interval

Withdrawn alive during interval*

Alive at beginning of interval

Died during interval

Patients diagnosed 193549 0- 6 months 6-12 ,, 12-18 ,, 18-24 ,, 24-30 ), 30-36 ,, 3642 ,, 4248 ,, 48-54 ,, 5460 O- 5 ye& 5-10 ,)

1135 364 175 95 68 54 45 39 34 31 1135 26

769 189 80 26 13 9 6 5 3 4 1104 8

Patients diagnosed 1950-56 0- 6 months 612 ,, 12-18 ,, 18-24 ,, 24-30 ,, 30-36 ,, 3642 ,, 4248 ,, 48-54 ,, 54-60 0- 5 ye&

1631 723 340 185 107 83 63 48 40 32 1631

798

104

326 117 50 9 14 7 5 4 2 1332

56 36 27 13 5 8 3 4 8 264

2 1 1 -

-

-

-

-

1 5 -

13

7

*Alive on closing date of study, 31st December 1956.

Survival experience

Figures 3 and 4 show the survival experience in 10 years of follow-up of the 933 male and 202 female patients with lung cancer diagnosed between 1935 and 1949. The logarithmic scale used for plotting the percentage of survivors at the end of successive follow-up years permits visual evaluation of the rate of depletion (mortality). The very steep slope of the initial part of the observed line tells how badly these patients fared: only 3 1.8 per cent of the males and 34.2 per cent of the females survived 6 months with the l-year survival rate, 14.6 and 19.3 ; and 5 years, 2.0 for males and 4.4 for females, respectively. For comparison, the expected survival experience for a group of persons from the general population with an age distribution similar to that of the patient with lung cancer is shown. Visually, the observed and expected slopes are

1038

HENRY EISENBERG,JAY M. SHAMES, WESLEY L. HOLLOWAY and HAROLD S. BARRETT

I

‘0

;

2

3 1

41

5j

Years after

61

!

:

7

8

9-

diagnosis

FIG. 3. Observed and expected survival rates for 10 years of follow-up. Male patients with cancer of the bronchus and lung diagnosed in Connecticut, 1935-49.

roughly parallel for men and women after 5 years. This would indicate that after 5 years the excess mortality had been eliminated. At that point, however, over 96 per cent of the patients had died; consequently little statistical significance can be placed on the small number of survivals. The relative annual survival rates shown in Fig. 5 provide a more precise measure of the relationship between the observed and the expected survival rates in successive follow-up periods. This rate is the ratio of the observed to the expected survival rate. A relative survival rate of 100 per cent means that during the specific follow-up interval the mortality rates in the patient group and in the general population were equal. The attainment and maintenance of such rates in patient groups equal to that in the general population would indicate that the excess mortality associated with cancer had been eliminated. Figure 5 shows that the annual relative survival rates for males increase sharply from the 6-month value of 32 per cent to the 30-month value of 85 per cent. After this point, the slope gradually increases and after 5 years, it approximates 95 per cent. A similar trend is noted in females. Only 26 of the original 1135 patients with lung cancer remain in the study after the first 5 years; the relative rates from the 4th to the 10th years are not reliable statistically because of the small number of cases. Variation by sex Table 3 compares the crude and relative survival rates for males and females for the 5-year period following diagnosis. It can be noted in the first group (1935-1949) that

Cancer of the Bronchus and Lung: Connecticut

1935-1959

Observed

Ll

b

PIG. 4.

,

I

2

I

3

:

’

’

4

5

Years

after

I

6

!

j

71

8

I

9

IC

diagnosis

Observed andexpected survival rates for 10 years of follow-up. Female patients with cancer of the bronchus and lung diagnosed in Connecticut, 193549.

100

1039

1040

HENRY EISENBERG,JAY M. SHAMES,WESLEY L. HOLLOWAY and HAROLD S. BARRETT

TABLE 3.

TEN YEARSOF SURVIVALEXPERIENCE, BY SEX. PATIENTSWITH CANCEROF THE BRONCHUSAND LUNG DIAGNOSED IN CONNECTICUT 1935-49 AND 1950-56’ (Rates are expressed as percentages) MALES

FEMALES

Crude rate

Relative rate

SE.

Crude rate

Relative rate

S.E.

1935-49 0- 6 months O-12 ,, O-18 0- 5 ye& I- 5 2, O-10 ,,

31.8 14.6 7.5 2.0 13.7 1.3

32.3 15.1 7.9 2.4 15.9 1.9

1.5 1.0 1.0 0.5 3.1 0.5

34.2 19.3 12.4 4.4 22.8 3.2

34.7 19.8 12.9 5.1 25.0 4.3

3.5 3.0 2.5 1.5 6.5 1.5

195&56 0- 6 months O-12 ,, O-18 0- 5 yek 1- 5 ,,

50.0 26.0 16.2 5.7 21.9

50.8 26.9 17.0 6.8 25.9

1.5 1.5 1.0 1.0 3.4

45.4 27.2 19.1 5.5 20.2

46.0 27.8 19.8 6.2 21.4

3.5 3.5 3.0 3.0 10.3

*Rates in italics have standard errors greater than 5.0. are shown but are statistically unreliable.

Rates with standard errors of 10 .O or larger

the females have a significantly higher survival rate than the males for all survival periods. This is in keeping with the results reported by EDERER and MERSCHEIMER [ 171. However, for the period, 1950-1956, the difference is less marked and in fact, the crude and relative survival rates for the male and female population are very similar. Secular trend

Few authors have noted any marked improvement in the rate of survival from lung cancer in recent years. Regardless of the period of time or of author reporting, 5-year survival rates generally vary between 3 and 10 per cent. It is of interest to compare the results in Connecticut for the two time periods. The changes in survival time are evaluated in Connecticut, both in terms of the crude and the relative cumulative survival rate. The relative survival rate corrects for any decrease in deaths from other causes during the second period resulting from the lowering in general mortality in recent years, and also corrects for any increase in death from other causes resulting from the increasing age of the population with lung cancer. Because of the short duration of survival for patients with lung cancer, normal mortality plays a minor role, and the crude and relative rates for intervals begnming at diagnosis are quite similar. Although the mortality among patients diagnosed in the second time period was also exceedingly high, there was some improvement over the first period. For men, the 6-month relative survival rate increased from 32 per cent to 51 per cent; the increase at the end of one year was from 15 per cent to 27 per cent; and for the 5-year period was from 2 per cent to 7 per cent. For women, the corresponding increases were from 35 per cent to 46 per cent, 20 per cent to 28 per cent, and 5 per cent to 6 per cent. It is noteworthy that the major part of the improvement in the 5-year survival occurred in the first 6 months of survival. This improvement is interpreted in the section on treatment.

Cancer of the Bronchus and Lung: Connecticut

1041

193551959

Variation by stage of disease

Classification according to stage of disease is based on all available information at discharge from the hospital. Those tumors staged as localized met the criteria of a disease process which is strictly confined to the bronchus or parenchyma of one lung with no evidence of metastases. There has been no breakdown into either regional or distant metastases. Table 4 shows the number and percentage of cases which were classified as localized. Table 5 shows the 6-month, l-year, and 5-year crude and relative survival rates for the male and female cohort groups comparing the localized cases to the entire group. It can be seen that the stage of disease is an important factor TABLE 4.

STAGE DISTRIBWIION BY PERIOD OF DIAGNOSIS. PATIENTS WITH CANCER OF THE BRONCHIJS ANDLIJNGDIAGNOSEDINCONNECTICUT 193549~~~ 1950-56

All stages

Localized

1935-49 Number of cases

1135 (100%)

307 (27%)

1950-56 Number of cases

1631 (100%)

395 (24%)

TABLET. CRUDE AND RELATIVESURVIVALRATESBYSTAGEOFDISEASE AND PERIOD OF DIAGNOSIS. PATIENTS WITH CANCER OF THE BRONCHUS AND LUNG DIAGNOSED IN CONNECTICUT, 193549 AND

1950-56 (Rates are exmessed as oercentages) All stages* Sex and follow-up interval for both periods of diagnosis

Localized

Crude survival rate

Relative survival rate

Crude survival rate

Relative survival rate

31.8 50.0

32.3 50.8

45.0 61.5

45.8 62.6

O-l year 1935-49 1950-56

14.6 26.0

15.1 26.9

24.2 39.6

25.0 41.0

O-5 years 1935-49 195&56

2.0 5.7

2.4 6.8

3.9 14.5

4.7 17.5

FEMALES O-6 months 1935-49 1950-56

34.2 45.4

34.7 46.0

45.8 64.7

46.4 65.5

O-l year 193549 1950-56

19.3 27.2

19.8 27.8

31.2 51.8

32.0 53.0

O-5 years 193549 195&56

4.4 5.5

5.1 6.2

13.6 26.4

15.5 29.7

MALES O-6 months 1935-49 1950-56

*Includes ‘stage unspecified.’

1042

HENRY EISENEZRG, JAY M. SHAMES,WESLEYL. HOLLOWAYand HAROLD S. BARRETT

in prognosis especially in the later cohort and more specifically in the females. The Both for localized cases had a significantly better outlook than the overall group. patients with localized disease and the entire group, rate of survival improved from the first to the second period.

Delay before treatment It is surprising to note in Table 4 that the percentage of localized cases in the 19351949 group was 27 per cent, whereas that for the 1950-1956 group was only 24 per cent. It is generally believed that delay before treatment is a crucial factor in the management of lung cancer. Lung cancer is a rapidly progressing disease; therefore early diagnosis and treatment are of the utmost importance. A major factor in the delay before treatment is that the first symptom is usually cough. Since many of the patients have chronic bronchitis [22] preceding the cancer, the symptom of cough is frequently overlooked and therefore there is considerable delay before the onset of more alarming symptoms such as chest pain, weight loss, or hemoptysis. Although there is no supporting evidence, a number of authors have claimed that cancer education campaigns in recent years have increased the alertness of patients and physicians to the symptoms of cancer, shortening the delay between the onset of symptoms and the diagnosis. The Connecticut data contains no information on the interval from the onset of the symptoms to treatment, but earlier case finding might be reflected in the percentage of cases classified as localized at diagnosis. The slight decrease or even lack of increase in the percentage of localized cases therefore is alarming.

Type of treatment The patients were classified into the following categories according to the treatment they received during the first course of medical care: surgery, radiation, surgery plus radiation, chemotherapy, and no treatment. Treatment, as defined by the Connecticut Tumor Registry, consists of procedures directed toward the tumor, whether for cure or palliation. Thus, an exploratory thoractomy would not be considered treatment, whereas a lobectomy in the face of distance metastases would be so cansidered. The data at hand contains no information on the extent (pneumonectomy or lobectomy) or the intent (cure or palliation) of the surgery. Table 6 shows that the percentage of patients treated surgically has increased markedly while the use of radiation and chemotherapy has remained about the same. It also can be seen that the percentage of patients receiving no treatment has dropped significantly. Survival of patients with cancel of the bronchus and lung, according to the treatment given during the first course of medical care, and by sex and period of diagnosis is demonstrated in Table 7. Only relative survival figures are shown since the crude rates were nearly identical to these. It should be remembered that a small number of patients were treated by chemotherapy, and by radiation plus surgery; this is evident by the large standard error. When comparing the 1935-1949 group with the 1950-1956 group, the increase in survival of those patients receiving no treatment is notable. In the first group, only 21 per cent of the males and 18 per cent of the females lived 6 months and 8 per cent of the males and 10 per cent of the females lived one year; for the second group, 33 per

Cancer of the Bronchus and Lung: Connecticut

1935-1959

1043

TABLE 6. PERCENTAGEDLSTIUBU-IION ACCORDINGTO TREATMENT DURING FIRSTCOURSEOF THERAPY, BY SEXAND PERIODOF DIAGNOSIS.PATIENTSWITH CANCEROF THEBRONCHUSAND LUNG DIAGNOSEDIN CONNECTICUT,1935-56

Percentages

of total number of cases -

Total number of cases

Histologically Males 193549 195&56 Females 1935-49 1950-56

Surgery plus radiation

Chemical and/or hormonal therapy

Not treated

Surgery

Radiation

933 1420

13.8 29.0

28.8 21.0

3.6 5.0

0.8 1.0

53.0 34.0

202 211

12.9 21.0

23.3 25.6

1.0 5.2

1.0 0.5

61.9 41.7

confirmed

only

cent of the males and 23 per cent of the females lived 6 months and 15 per cent of the males and 13 per cent of the females lived one year. This increase in survival must be interpreted only after considering at least two points. First, the number of cases receiving no treatment in the 1935-1949 group was significantly greater than those in the 1950-1956 group. Secondly, those patients who received no treatment were selected by their physician rather than randomly being placed into this category, and the possible reasons for this selection would enter into their survival. Nevertheless, it appears that something other than the type of definitive therapy plays some part in increasing the survival of these patients; one must consider the possible influence that supportive measures such as steroids and antibiotics have exerted in the latter time period. It can be seen that by far the best results were seen in those patients who had surgery. The one-year relative survival rate for the males in the first group (19351949) treated by surgery was 40 per cent as opposed to 8 per cent for those receiving no treatment; for those in the second group (1950-1956) it was 50.5 per cent, as opposed to 15 per cent; for those females in the first group treated surgically and surviving one year the relative rate was 58.5 per cent as opposed to 10 per cent for those receiving no treatment; and in the second group the figures were 59 per cent and 13 per cent. respectively. It can be seen that there were no 5-year survivors in the patients that were untreated in the first group, whereas 13.6 per cent of those receiving surgery survived 5 years, and 11.6 per cent survived 10 years; the 5-year survival rate for males in the second group was 20 per cent for those receiving surgery, as opposed to 1 per cent for those receiving no treatment. The figures are even more remarkable for the females. In females diagnosed between 1935-1949, only 1 per cent of those who received no treatment lived 5 years, whereas 32 pet cent of those treated surgically lived 5 years; in the second group, there were no 5-year survivors among those who received no treatment and there was a 17 per cent survival rate for those treated surgically. It should also be noted that although the survival figures for patients receiving radiation are considerably lower than those receiving surgery, they do show improvement over those receiving no treatment and consequently suggest a palliative effect. It is also notable that there is no significant increase in the survival rates of those patients receiving radiation plus surgery over those receiving surgery alone. It must be remembered however, that the Connecticut data do not specify the type of surgery or the dose of

50.8 26.9 17.0 6.8 25.9

34.7 19.8 12.9 5.1 25.0 4.3

46.0 27.8 19.8 6.2 21.4

1950-56 0- 6mth 0- 1 yr O-l 8 mth 0- 5 yr l- 5yr

Females 1935-49 0- 6mth 0- 1 yr O-18 mth 0- 5 yr l- 5yr O-10 yr

1950-56 @- 6 mth o- 1 yr O-18 mth @ 5 yr l- 5yr

3.5 3.5 3.0 3.0 10.3

3.5 3.0 2.5 1.5 6.5 1.5

1.5 1.5 1.0 1.0 3.4

1.5 1.0 1.0 0.5 3.1 0.5

22.9 12.9 6.2 -

17.9 9.9 4.2 0.9 10.0 -

32.6 15.0 5.8 0.9 6.7

21.5 8.1 2.4 -

rate

-

4.5 4.0 3.0 -

3.5 2.5 2.0 1.0 9.7 -

2.0 2.0 1.0 0.5 3.2

2.0 1.5 0.5 -

(Rates

80.6 59.2 50.6 17.3 28.8

77.5 58.5 58.9 32.0 54.2 25.1

71.4 50.5 38.3 20.1 39.2

51.9 39.9 30.8 13.6 35.0 11.6

rate

5.5 7.0 7.0 8.0 13.1

8.5 10.0 10.0 10.0 14.2 10.0

2.5 2.5 2.5 3.0 5.6

4.5 4.5 4.0 3.5

-

44.6 17.1 6.5 -

53.8 23.9 8.8

17.0 8.2

49.0

38.8 13.8 5.8 0.5 3.6 -

rate

7.0 5.5 3.5 -

7.5 6.5 4.0

2.5 2.0 1.5 -

3.0 2.0 1.5 0.5 3.4 -

62.3 39.8 40.0 -

50.2 50.3

50.1

64.4 30.6 20.9 2.3 6.4

65.4 36.0 18.1 9.8 27.8 7.6

rate

16.0 16.0 -

15.0

35.5 35.5 35.5 -

5.5 5.0 2.0 6.3

6.0

8.5 8.5 6.5 5.5 13.8 5.0

*Rates in italics have standard errors greater than 5.0. Rates with standard errors of 10.0 or larger are shown but are statistically umliable.

32.3 15.1 7.9 2.4 15.9 1.9

rate

Total, treated

Males 1935-49 0- 6mth 0- 1 yr O-18 mth 0- 5yr l- 5yr O-10 yr

period of diagnosis

-

-

35.5 -

-

50.2

13.5 -

13.5 -

S.E.

39.2 -

-

-

14.5

rate

TABLE 5. TEN YEARS OF SURVIVAL EXPERIENCE, ACCORDING TO TREATMENT DURING FIRST COURSE OF THERAPY, BY SEX AND CALENDAR PERIOD OF DIAGNOSIS PATIENTS WITH CANCEROFTHEBRONCXIUSANDLLJNGDIAGNOSEDIN Co~~~crrcu~ 193549 AND 1950-56*

Cancer of the Bronchus and Lung: Connecticut

1935-1959

104.5

radiation received and therefore this may qualify to some degree the lack of difference. Of notable interest in Table 7, is the sizable increase, from the first period to the second, in the survival rates for males regardless of the method of therapy but most notably in surgery, whereas for females this observation does not hold true. Although there is a slight increase in the overall survival rates for females, the survival rates for the specific types of therapy show somewhat of a decrease between the two time periods. In order to explain the overall increase in survival for the females one must conclude that this difference is due to the decrease in number of patients not treated and an increas: in the number of patients treated. It can be seen that approximately 25 per cent of the patients who survived one year following therapy were still alive 5 years following therapy while about l/3 of the patients who underwent surgery and lived one year, went on to live for 5 years. Almost all the patients surviving 5 years, lived for 10 years after their therapy, giving some credibility to the term ‘5-year cure.’

Age To evaluate the relationship between survival and age, normal survival expectancy was taken into account. Table 8 shows the 18-month relative survival rates by age and diagnosis for each of the five age groups and the corresponding crude rates. By noting the age distribution listed on Table 1 it is apparent that there is a larger percentage of females under the age of 45 and over the age of 75, as compared to the males. It is also apparent that the survival rates for these two age groups are based on a comparatively small number of patients. It can be observed in Table 8 that there appears to be a difference in the age pattern of survival rates between males and females. In the 1935-1949 group, males under the age of 45 had a very poor survival rate; the rate for females during this same time period was 12 times as great. It can be seen that as females increase in age, there is a decrease in the survival rate; male survival rates seem to increase to the interval of 55-64 years of age, and then decrease. If the rates for those patients under 45 years of age were disregarded, the difference between the male and female survival rates would be minimal. It is interesting to postulate a possible hormonal influence which induces the tremendous change in the survival rates between the men and women under the age of 45 years. Histological type The distribution of lung cancer by histological type, sex, and period of diagnosis is given in Table 9. These cases have been placed into the following three categories : (1) squamous cell, (2) adenocarcinoma, (3) all other histological types. Included in the category of all other histological types are the oat-cell variety, which is only about 5 per cent of this group, undifferentiated carcinoma, and bronchogenic carcinoma not otherwise specified. It can be seen that squamous cell and the category of all other histological types, each compose about 40 per cent and adenocaicinoma consists of about 20 per cent of the entire group. This compares well with data reported by others [lo, 19, 211. It is apparent that there is little change in the histological types of lung cancer between the males of the two groups. It appears however, that there is a decrease in the percentage of squamous cell and an increase in the amount of adenocarcinoma in the females during the latter period of time. It can be noted that although adenocarcinoma makes up a larger percentage of the total amount of lung cancer in

25.6 29.2

Females Treated and not treated combined 1935-49 1950-56

25.7 29.3

2.2 18.2

Relative rate

6.5 9.0

1.5 5.0

S.E.

10.9 17.6

6.9 21.4

Crude rate

11.0 17.7

7.0 21.7

Relative rate

45-54

4.5 6.0

1.5 2.5

S.E.

10.7 20.5

9.5 16.5

Crude rate

11.0 20.9

9.9 17.1

Relative rate

55-64

4.5 5.5

1.5 2.0

S.E.

8.1 lg.6

7.3 12.2

Crude rate

8.6 19.5

8.0 13.2

Relative rate

65-14

*Rates in italics have standard errors between 5.0 and 9.9. Rates with standard errors of 10.0 or larger are not shown.

2.2 18.1

Males Treated and not treated combined 1935-49 1950-56

Crude rate

Under 45

5.0 6.0

2.0 2.0

S.E.

8.5

5.9 14.5

9.9

7.2 17.1

75 and over ~Crude Relative rate rate

7.5

5.0 5.5

SE.

EIGHTEEN-MONTH SURVIVALRATES BYAGE, CALENDAR PERIODOF DIAGNOSIS AND SEX. PATIENTSWITHCANCEROF THEBRONCHUS ANDLUNGDIAGNOSED IN CONNECTICUT,193%56* (Rates are expressed as percentages)

Sex, and period of diagnosis

TABLE8.

Cancer of the Bronchus and Lung: Connecticut TABLE 9.

CASE CANCER

Histological

1935-1959

1047

BY SEX,HISTOLOGICAL TYPESAND PERIODOF DIAGNOSIS. PATIENTSWITH OF THE BRONCHUSAND LUNG DIAGNOSEDIN CONNECTICUT, 1935-56 (Percentage distribution is given in parentheses) Both sexes

type

Males

Females

933 (82.2) 1420 (87.1)

202 (17.8) 211 (12.9)

All types (1935-49) All types (1950-56)

1135 (100) 1631 (100)

Squamous cell Adeno carcinoma All other types Total

530 (46.7) 187 (16.5) 418 (36.8) 1135 (100)

Squamous cell Adenocarcinoma All other types Total

681 (41.7) 296 (18.2) 654 (40.1) 1631 (100)

1950-56 591 (41.6) 218 (15.4) 611 (43.0) 1420 (100)

cell carcinoma

is the major histological

females

than in males,

squamous

193549 416 (44.6) 140 (15 .O) 337 (40.4) 933 (100)

114 47 41 202

(56.4) (23.3) (20.3) (100)

90 78 43 211

(42.6) (37.0) (20.4) (100)

type in both

sexes. The

stage distribution

lung cancer

by microscopic

for each period

confirmation

of time is shown

at diagnosis

for

patients

with

in Table 10. There does not appear to be any major difference in the percentage of cases with localized tumors of any histological type. Adenocarcinoma is the only histological type where an increase is shown in the percentage of cases staged as localized. Table 11 summarizes the percentage distribution according to treatment duting the first course of therapy by histological type, sex and period of diagnosis. For each histological type and for both males and females there is a marked increase in the use of surgery between the 19351949 group and the 1950-1956 group. For this latter period of time, about 20 per cent of the squamous type, 33 per cent of the adenocarcinema type, and 35 per cent of all the other histological types underwent surgery. There has been a decrease of about 20 per cent in the number of untreated cases in each histological type. It is apparent that there is still about 40 per cent of the squamous type carcinoma which is going untreated. The decline in untreated adenocarcinoma in males is quite marked-from 57 per cent to 28 per cent-whereas that for females is only 59 per cent to 46 per cent. This marked difference between males and females in the percentage of untreated patients with adenocarcinoma for the 1950-1956 period appears to be related to the use of radiation in that period; 30 per cent of the males and and only 15 per cent of the females received radiation for adenocarcinoma, whereas the percentages receiving surgery are almost identical. The relative survival rates by treatment, sex, histological type and period of diagnosis during the first course of medical care are listed in Table 12. It must be remembered that in subdividing this group into the categories used in Tables 11 and 12, one is working with a relatively small number of patients. This does limit the statistical significance that can be placed on these figures. By looking at all histological types of lung cancer, treated and untreated, it can be seen that there is no histological type in which the 5-year survival rate is greater than 10 per cent, and that each histological type has a better prognosis when surgical treatment is possible. It appearsthat squamous

HENRY EISENBERG, JAY M. SHAMES,WESLEY L. HOLLOWAYand HAROLD S. BARRETT

1048

TABLE 10. STAGE DISTRBWION BY HISTOLOGICAL TYPE, SEX AND PERIOD OF DIAGNOSIS. PATIENTS WITH CANCER OF THE BRONCHUS AND LUNG DIAGNOSED IN CONNECTICUT 1935-49 AND 1950-56 No. and % of patients by period

Localized

All stages Total

Males

Females

Total

Males

Females

Squamous 193549 No. %

530 100.0

416 100.0

114 100.0

132 24.9

103 24.8

29 25.4

1950-56 No. %

681 100.0

591 100.0

90 100.0

137 20.1

124 21 .o

13 14.4

Adenocarcinoma 1935-49 No. %

187 100.0

140 100.0

47 100.0

34 18.2

24 17.1

10 21.3

1950-56 No. %

296 100.0

218 100.0

78 100.0

80 27.0

59 27.1

21 26.9

All other histological types 1935-49 No. %

418 100.0

377 100.0

41 100.0

141 33.7

132 35.0

9 21.9

1950-56 No. %

654 100.0

611 100.0

43 100.0

178 27.2

168 27.5

10 23.3

cell type may offer a slightly poorer prognosis does not seem to be any consistent difference and females for histological types.

than the other histological types. There between the survival rates of the males

DISCUSSION

It has been widely reported that bronchogenic carcinoma, prior to 1930, was a rare disease. In the past 30 years, this malignancy has risen to become one of the most common, if not the most common cancer in man. Other authors [lo, 20,24,25] have attempted to demonstrate that there is a real increase of this malignancy and to relate this increase to the increase in cigarette smoking. The data presented herein for Connecticut do not contain any figures on the prevalence of cigarette smokers; however, it is noted that there has been a tremendous increase in the incidence of bronchogenie carcinoma. It has been stated in the literature that of all patients seen with bronchogenic cancer, only 50 per cent are considered eligible for operation. Of those who undergo surgery, only 50-60 per cent of lesions are resectable; of those patients who have a resectable lesion, only 25-30 per cent survive 5 years. This gives an overall 5-year survival rate of less than 5 per cent, for all patients who are diagnosed as having lung cancer [15]. This statement is upheld by reviewing the literature, for the resectability rate varies between 5 and 45 per cent, with an average of about l/3 of all patients being eligible for

Cancer of the Bronchus and Lung: Connecticut

1935-1959

1049

TABLE 11. PERCENTAGEDISTRIBUTION ACCORDING TO TREATMENTDURINGFIRST COURSEOF THERAPY, BYSEXAND PERIODOFDIAGNOSIS. PATIENTS WITH CANCEROF THEBRONCHUSANDLUNGDIAGNOSED IN CONNECTICUT~~~~--56

Total number of patients

% of total number (no. of cases in therapy group) _______ Surgery Chemical Surgery Radiation PIUS and/or Not radiation hormonal treated therapy Squamous

Males 1935-49 1950-56

416 591

8.6 (36) 19.5 (115)

28.8 (120) 35.4 (209)

Females 193549 1950-56

114 90

10.5 (12) 20.0 (18)

23.7 (27) 34.4 (31)

2.2 (9) 3.5 (21)

0.7 (3) 1 .5 (9)

59.6 (248) 40.1 (237)

0.9 (1) 3.3 (3)

0.9 (1) 0

64 (73) 42.2 (38)

Adenocarcinoma Males 1935-49 1950-56

140 218

12.9 (18) 33.9 (74)

24.3 (34) 29.4 (64)

5.0 (7) 6.4 (14)

0.7 (1) 1.8 (4)

57.1 (80) 28.4 (62)

Females 1935-49 1950-56

41 78

12.8 (6) 33.3 (26)

23.4 (11) 15.4 (12)

2.1 (1) 5.1 (4)

2.1 (1) 0

59.6 (28) 46.2 (36)

All other histological types Males 193549 1950-56

371 611

19.9 (75) 37.2 (227)

30.5 (115) 27.2 (166)

4.8 (18) 6.5 (40)

0.8 (3) 0.3 (2)

44.0 (166) 28.8 (176)

Females 1935-49 1950-56

41 43

19.5 (8) 30.2 (13)

21.9 (9) 25.6 (11)

0 9.3 (4)

0 2.3 (1)

58.5 (24) 32.6 (14)

[13-16, 26-321. In Connecticut, the resectability rate was about 15 pet cent for either sex in the 1935-1949 group and 33 per cent for the 1950-1956 group. Trying to compare results reported by the various investigators is quite difficult because one is never sure that the patients in the various series are really comparable. Superior results achieved in one treatment center as contrasted with another may be due to differences in characteristics of the two patient groups with respect to age, race, socio-economic status, general clinical condition, method of patient selection, and the extent of cancer at diagnosis. It can be easily understood that the figures from the State of Connecticut will differ considerably from those reported from the Veteran’s Administration Hospital in Hines, Illinois [26] and those reported from the Lahey Clinic [13, 141 or the Ochsner Clinic [ 1 I] for the above stated reasons and probably others. In spite of the increasing awareness of this disease, evidence pointing to earlier detection is lacking. There has been no increase in the number of localized tumors between the two time periods. The insidious onset of this condition is probably responsible for this. Boucor reports that in her screening project in Philadelphia, only 10 per cent of bronchogenic cancer was asymptomatic [33]; in her series of 250 patisnts, the resection rate was only 29 per cent [32].

resection

1050

HENRY EISENBERG,JAY M. SHAMES,WESLEYL. HOLLOWAY and HAROLD S. BARRETT

TABLE 12. RELATIVESURVIVALRATESBY TREATMENTDURING FIRSTCOURSEOF MEDICALCARE, SEX, HISTOLOGICAL TYPES,AND PERIODOF DIAGNOSES.PATIENTSWITH CANCEROF THEBRONCHUS AND LUNG DIAGNOSED IN CONNECTICUT,1935-56*

Sex, period of diagnosis and follow-up interval

Total treated and not treated Relative survival rate

S.E.

Surgically treated only Relative survival rate

Not treated

S.E.

Relative survival rate

SE.

Squamous Males 1935-49 0- 6 mth O-12 mth O- 5 yr

24.3 11.3 0.8

2.0 1.5 0.5

39.4 25.7 6.5

8.0 7.5 4.5

18.9 7.2 -

2.5 1.5 -

1950-56 0- 6 mth O-12 mth 0- 5 yr

41.4 19.3 3.5

2.0 2.0 1.0

62.3 39.8 11.9

4.5 5.0 4.5

29.5 12.9 1.0

3.0 2.5 1.0

Females 1935-49 0- 6 mth O-12 mth 0- 5 yr

27.6 14.4 5.1

4.0 3.5 2.0

75.5 59.1 44.9

12.5 14.5

15.5

11.2 5.1 -

3.5 3.0 -

1950-56 O-6 mth &12 mth 0- 5 yr

35.4 20.4 5.6

5.0 4.5 3.5

67.2 62.0 17.4

11.0 11.5 11.0

17.6 9.0 -

6.5 5.0 -

Adenocarcinoma Males 1935-49 0- 6 mth O-12 mth 0- 5yr

27.5 8.2

4.0 2.5 -

28.2 17.2 -

10.5 9.0 -

12.7 5.2 -

4.0 2.5 -

1950-56 0- 6 mth O-12 mth 0- 5 yr

54.7 27.8 8.2

3.5 3.0 2.5

77.5 51.3 23.8

Z 6.5

32.8 16.7 -

6.0 5.0 -

Females 1935-49 0- 6 mth O-12 mth 0- 5 yr

47.5 39.4 5.5

7.5 7.5 3.5

83.6 83.9 17.3

15.5 15.5 16.0

40.0 29.6 4.3

9.5 9.0 4.0

1950-56 0- 6 mth O-12 mth 0- 5 yr

53.9 29.6 6.1

6.0 5.5 5.5

84.5 60.8 16.5

7.5 IO.5 14.0

29.0 13.1 -

7.5 6.0

Cancerof the Bronchus and Lung: Connecticut

19351959

1051

TABLE 12-Continued

Sex, period of diagnosis and follow-up interval

Total treated and not treated _ Relative S.E. survival rate

Surgically treated only Relative survival rate

S.E.

Not treated Relative survival rate

S.E.

All other histological types Males 1935-49 0- 6 mth O-12 mth 0- 5 yr

42.8 21.9 5.0

2.5 2.0 1.0

63.6 52.2 20.4

5.5 6.0 5.0

29.4 10.6 -

3.5 2.5 -

1950-56 0- 6 mth O-12 mth & 5yr

58.5 33.7 9.6

2.0 2.0 2.0

74.0 55.7 23.8

3.0 3.5 4.5

36.9 17.2 1.1

3.6 3.0 1.0

Females 1935-49 0- 6 mth O-12 mth 0- 5 yr

39.4 12.4 4.9

7.5 5.0 3.5

75.8 38.3 28.1

15.5 17.5 17.0

12.6

7.0 -

1950-56 & 6 mth O-12 mth 0- 5yr

53.4 39.2 -

7.5 7.5 -

92.7 51.0 -

7.5 14.5

21.8 22.1

-

11.0 11.5 -

*Rates in italics have standard errors greater than 5 .O. Rates with standard errors of 10.0 or larger are shown but are statistically unreliable.

The fact that

cancer

of the lung is a highly lethal disease cannot be disputed. a 5-year survival rate of 2.8 per cent in 360 untreated cases whereas BURFORD et al. [29] and GIBBON et al. [27, 281 record no 5-year survivors. In the present series in Connecticut, less than 1 per cent of those patients with untreated bronchogenic carcinoma survived 5 years. When considering all patients with lung cancer, treated and not treated, Connecticut figures do not show better than a 7 per cent 5-year survival rate. The reports in the literature of an overall survival rate of greater than 10 per cent are rare. The findings from this study appear to demonstrate that the only method of therapy which seems to hold any promise is surgery. Uniformly poor results are recorded for radiation and chemotherapy. Connecticut figures for surgically-treated lung cancer patients give a 5-year survival rate between 20 and 25 per cent, which compares well with that reported by many other centers. One must take into consideration the fact that the mode of therapy selected for these patients was that deemed most advantageous by their physician rather than being selected on a random basis. JOHNEON [30] reports 80 per cent 5-year survival rate for patients treated surgically who had neither blood vessel nor lymphatic invasion at the University of Pennsylvania Hospital. There are numerous reports of survival rates over 35 per cent for surgical For Connecticut, the 5-year survival rate for treatment of localized lesions. localized lung cancer was 29.7 per cent for females and 17.5 per cent for the EMERSON et al. [ 191 reports

1052

HENRY EISENBERG,JAYM. SHAMES, WESLEY L. HOLLOWAY and

HAROLD S. BARRE=

males. As reported by EDERERand MERSHCEIMER [17], Connecticut figures also show that females have a higher survival rate than do men, although in the group of patients diagnosed between 1950 and 1956, this difference was not remarkable. MERSCHEIMER [34] observed that “the outlook for the patient with cancer of the bronchus and the lung continues to be grim, unless the disease is localized and treated surgically. The most discouraging aspect is that there is no evidence of any trend toward an earlier diagnosis during the past two decades. Advances in supportive and surgical techniques have enabled the surgeon to treat an increasing number of patients that previously may have been considered inoperable and this has resulted in a noteworthy gain.” OVERHQLT[35] says, “Until chemotherapy, radiation or some other weapon proves to be effective for destruction of malignant cells in this location, extirpation of the lesion is necessary if cure is to be the objective.” BOUCQT[33] has stated that “efficacy of treatment must be based on sound knowledge of the course of the untreated disease. The natural history of lung cancer starts at a time when there are no symptoms or radiological abnormalities. ‘ . . . the only feasible approach to those without symptoms is to take periodic X-ray films of chests, of asymptomatic populations of known high lung cancer prevalence-older men particularly those who have smoked cigarettes heavily for more than 40 years.’ Any abnormality in the chest X-ray of an older man should be suspected of malignancy, if not promptly proved non-malignant.” This Connecticut series seems to echo these words: bronchogenic cancer is a rapidly fatal disease, offering little chance of survival regardless of the method of therapy. It appears that the key to controlling this now epidemic disease process is through prophylactic measures and early detection. SUMMARY A marked increase has been noted in the incidence of cancer of the bronchus and lung in Connecticut. The incidence of this malignancy in males has risen from 8.7 per 100,000 population in 1935, to 46.7 per 100,000 in 1959; the corresponding figures for females demonstrate a rise from 4.1 to 7.3 per 100,000 population. A detailed 22-year survival analysis by stage, age, histological type, calendar period of diagnosis, and type of treatment of patients with cancer of the bronchus and lung diagnosed in the state of Connecticut between 1935 and 1956 is presented _ Observed survival is measured relative to expected survival in the general population. Among patients, diagnosed during 1935-1949, only l/3 of those who were expected to survive the first 6 months after diagnosis, did in fact, survive; less than 20 per cent of these lived 1 year and less than 5 per cent lived 5 years. Patients diagnosed during 1950-1956, experienced only slightly higher 5-year survival rates than those diagnosed in 1935-1949; the relative lo-year survival rate for lung cancer is 4 per cent for females and 2 per cent for males. There does appear to be a slightly higher survival rate for females having bronchogenic cancer. The increase in survival rates from the 19351949 period to the 1950-1956 period was possibly related to the increase in the percentage of patients treated by surgical intervention. This study suggests that there is an increase in the survival time of the surgically treated patients. The survival figures for the state of Connecticut are similar to the average figures obtained in other treatment centers of the United States.

Cancer of the Bronchus and Lung: Connecticut

1935-1959

1053

REFERENCES 1. CUTLER,S. J., EDERER,F., GRISWOLD,M. H. and GREENBERG,R. A.: Survival of breast cancer patients in Connecticut, 1935-1954, J. nut. Cancer Inst. 23, 1137, 19.59. 2. CUTLER,S. J., EDERER,F., GRISWOLD,M. H. and GREENBERG,R. A. : Survival of patients with uterine cancer, Connecticut, 1935-1954, J. nut. Cancer

nut. Cancer Inst. 24, 541, 1960. 4. EDERER,F., CUTLER,S. J., EISENBERG,H. and KEOGH,J. R.: Survival of patients with cancer of the stomach, Connecticut, 1935-1954, J. nut. Cancer Inst. 25, 1005, 1960. 5. EDERER,F., CUTLER,S. J., EISENBERG,H. and KEOGH,J. R. Survival of patients with cancer of the large intestine and rectum, Connecticut, 1935-1954, J. nut. Cancer Inst. 26, 489, 1961. 6. GRISWOLD,M. H. and CUTLER, S. J.: The Connecticut cancer register; seventeen years of experience, Conn. med. J. 20, 366, 1956. 7. GREENBERG,R. A.: The Connecticut tumor registry, Conn. Hlth Bull. 73, No. 2, 1959. 8. GREENWOOD,M.: A Report on the Natural Duration of Cancer. Reports on Public Health and Medical Subjects, No. 33. H.M. Stationary Office, London, 1926. 9. DAVIES,D. F. and SEIDMAN,H.: The incidence and epidemiology of bronchogenic cancer, Proc. nut. Cancer Conf. 4,291, 1960. 10. OCHSNER,A., DECAMP, P. T., DEBAKEY,M. E. and RAY, C. J.: Bronchogenic carcinoma: its frequency, diagnosis, and early treatment, J. Amer. med. Ass. 149, 691, 1952. 11. OCHSNER,A., OCHSNER,A., Jr., HIDOUBLER,C. and BLALOCK,J.: Bronchogenic carcinoma, Dis. Chest 37, 1, 1960. 12. DEBAKEY,M. E.: The problem of carcinoma of the lung, Amer. Surg. 19, 1, 1953. 13. BOYD,D. P., SMEDAL,M. I., KIRTLAND,H. B., KELLEY,G. E. and TRUMP,J. G.: Carcinoma of the lung: a report of 403 cases, J. thoruc. Surg. 28, 392, 1954. 14. BOYD,D. P. : Carcinoma of the lung. A review of 628 cases, Surg. C/in. N. Amer. 39,677, 1959. 15. KIRILUK, L. B.: Carcinoma of the lung, Amer. J. Surg. 102,217, 1961. 16. WATSON,W. L.: Five-year survival in lung cancer-study of 3073 cases, Amer.J. Roentgen. 79, 488,1958. 17. EDERER,F. and MERSCHEIMER, W. L. : Sex difference in survival of lung cancer patients, Cancer 15,425, 1962. 18. SABOUR,M. S., OSMAN,L. M., GLEN, J., FAHY, T. and LAMB, P.: Carcinoma of the lungreview of 509 patients, Dis. Chest 41, 530, 1962. 19. EMERSON,G. L., EMERSON,M. S. and SHERWOOD, G. E. : The natural history of carcinoma of the lung, J. thoruc. Surg. 37,291, 1959. 20. HAMMOND,E. C.: The effects of smoking, Sci. Amer. 207,3, 1962. 21. BALO, J.: Aetiology of lung cancer and carcinoma of the lung, abstract in VIII Znt. Cancer Congr., p. 281, 1962. 22. AUERBACH,0. and STOUT,A. P. : The role of carcinogens, especially those in cigarette smoke in the production of precancerous lesions, Proc. nut. Cancer Conf. 4,297, 1960. 23. DOLL, R. and HILL, A. B. : Lung cancer and other causes of death in relation to smoking, Brit. med. J. 2, 1071, 1956. 24. ROYAL COLLEGEOF PHYSICIANS:Smoking and Health. Summary and report of the Royal College of Physicians of London on smoking in relation to cancer of the lung and other diseases. Pitman, New York, 1962.. 25. PUBLIC HEALTH SERVICE: Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service, 387 pp. U.S. Govt. Printing Office, Washington, 1964. 26. ARIEL, 0. et al.: Primary carcinoma of the lung. A clinical study of 1205 patients, Cancer 3, 229,195O. 27. GIBBON, J. H., TEMPLETON,J. Y. and NEALON,T. F.: Factors which influence the long term survival of patients with cancer of the lung, Ann. Surg. 145,637, 1957. 28. GIBBON,J. H., ALLBRIT~EN,F. F., TEMPLETON, J. Y. and NEALON, T. F.: Cancer of the lung: an analysis of 532 consecutive cases, Ann. Surg. 138,489, 1953. 29. BURFORD, T. H., CENTERS,S., FERGUSON,T. B. and SPJUT, H. J.: Results in treatment of bronchogenic carcinoma: an analysis of 1008 cases, J. thoruc. Surg. 36, 316, 1958. 30. JOHNSON,J., KIRBY, C. K. and BLAKEMORE, W. J.: Should we insist on ‘radical pneumonectomy’ as a routine procedure in the treatment of carcinoma of the lung, J. thoruc. Surg. 36, 309, 1958. 31. CHURCHILL,E. D., SLEET, R. H., SCANNEL,G. and WILKENS,E. W.: Further studies in the surgical management of carcinoma of the lung: a further study of the cases treated at the Massachusetts General Hospital (1950-1957), J. thoruc. Surg. 36, 301, 1958.

1054

HENRYEISENBERG.JAY M. SHAMES,WESLEYL. HOLLOWAYand HAROLDS. BARRETT

32. BOUCOT,K. R., HORIE, U. and SOKOLOFF, M. J.: Survival in lung cancer, New Engl. med. J. 260, 743, 1959. 33. BOUCOT,K. R.: The early detection of bronchogenic cancer, Proc. nut. Cancer Conf: 4, 305, 1960. 34. MERXHEIMER,W. L. and EDERER, F. : End results evaluation of cancer of the lung and bronchus, Proc. nut. Cancer Conf. 4,319, 1960. 35. OVERHOLT,R. H. : The surgical treatment of bronchogenic cancer, Proc. nut. Cancer Conf: 4,309, 1960.