Professional Documents
Culture Documents
From the Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Supported in part by a grant-in-aid for cancer research from the
Japanese Ministry of Health and Welfare (2-4).
The authors thank M. Motomiya for his kind criticism.
Address for reprints: Katsuo Usuda, M.D., the Department of
Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-Ku, Sendai 980, Japan.
Received January 7, 1994; revisions received April 11, 1994, and
June 20,1994; accepted June 20,1994.
2240
mas, 12 large cell carcinomas, 1 carcinoid, and 1adenosquamous carcinoma. Of the 126 patients with resected
lung cancer, 2 had a Stage I localized bronchioloalveolar carcinoma and 1 had a Stage I11 bronchioloalveolar carcinoma. In 48 patients who underwent nonsurgical treatment, diagnosis was made by cytology,
and the number of patients with a localized bronchioloalveolar carcinoma could not be confirmed.
A chest X-ray film taken at least 3 months before
the time when a tumor was detected was available for
all patients. The volume DT was calculated using the
Schwartz formula," as shown in Figure 1. Tumor size
was measured separately by two radiologists on posteroanterior roentgenograms. Interobserver difference
was less than 4 mm for a well defined tumor shadow
and 7 mm at the most for an ill defined tumor shadow.
DT was calculated based on the mean obtained by the
two observers. Intraobserver difference was less than 3
mm. Measurements were taken solely from the X-rays.
There was a strong correlation between the size of tumor on X-rays and the size of tumor measured by a pathologist after excision. The correlation coefficient was
0.9573 (P < 0.0001) in 69 patients who underwent resection and in whom a pathologic size of tumor was
recorded.
The minimum size of lung cancer that can be detected on a chest X-ray film has been reported to be 6
mm.1.3.11 Of the 174 patients, 136 had a tumor shadow
on a chest X-ray taken within 3-12 months before the
first detection of a lung cancer. Thirty-eight patients
had no tumor shadow on a chest X-ray taken within 312 months before the first detection of a lung cancer,
and an assumption was made that a tumor was there
and that its greatest dimension was 6 mm (being smaller
than the limit of detection) at the time when the reference film was taken. In the 38 patients, 34 had disease
detected by the annual screening trial in Miyagi Prefecture, and the last normal chest X-rays were taken in the
previous year. The mean duration of time between the
last normal chest X-ray and the measured abnormal
chest X-ray in the patients with disease detected by
screening was 12 months. Four other patients had dis-
2241
30L
1.5
2.0
2.5
3.0
(31.6)
(100)
(316)
(1 000)
LcglOScale
(days)
Log (DT)
Figure 2. Distribution after logarithmic conversion of DT. Skewness:
0.7204; kurtosis: -0.0643.
T factor
N factor
Men
Women
Detected by the screening trial
Detected when seen in hospital
With
Without
With
Without
Resection
Nonsurgical treatment
Adenocarcinoma
Squamous cell ca.
Small cell ca.
Large cell ca.
T1
T2
T3
T4
NO
N1
N2
N3
M factor
MO
M1
Stage
I
II
I11
Iv
GM
AMZSD
Category
(n = 123)
(n = 51)
(n = 129)
(n = 45)
(n = 101)
(n = 73)
(n = 85)
(n = 89)
(n = 126)
(n = 48)
(n = 86)
(n = 67)
(n = 7)
(n = 12)
(n = 63)
(n = 79)
(n = 19)
(n = 13)
(n = 86)
(n = 24)
(n = 54)
(n = 10)
(n = 158)
(n = 16)
(n = 73)
(n = 15)
(n = 70)
(n = 16)
126.4 t 133.5
253.5 2 232.1
162.5 ? 174.3
167.1 t 188.4
118.1 2 110.3
226.7 2 227.7
120.4 2 110.5
205.0 ? 216.2
175.3 2 190.3
133.0 ? 135.5
186.0
112.4
115.9
I*
IS
161.1
142.4
118.2
101.5
104.7 2 105.6
80.8 t 49.7
79.4 51.9
69.2
66.8
145.6 ? 177.8
139.0 Z 193.7
89.4
199.2 ? 207.5
135.0 -C 172.4
130.8 Z 127.2
104.1 55.5
165.2 ? 175.4
148.5 ? 202.4
212.7 -C 213.6 t
118.6 t 76.7
125.7 -t 129.4
148.5 2 202.4
132.8
93.7
99.4
93.2
115.0
98.3
144.3 t
100.3
93.4
98.3
AM 2 SD: arithmetic mean ? standard deviation; G M geometric mean; Ca: carcinoma; T factor: primary tumor
factor; N factor: regional lymph node factor; M factor: distant metastasisfactor.
* P < 0.001.
i P < 0.01.
$ P < 0.05.
2242
1%)
iO0' b.
80
(n=76)
1
Rapidly-growing (DT< 11 3.3 days)
(n=98)
pco.001
_I
significantly lower than that (52%) of 89 patients without symptoms. The 5-year survival rate (2%) of 48 patients who underwent nonsurgical treatment was significantly lower than that (55%) of 126 patients who
underwent resection.
The 5-year survival rate was 47% for 86 patients
with adenocarcinoma, 37% for 67 patients with squamous cell carcinoma, 28% for 7 patients with small cell
carcinoma, and 16% for 12 patients with large cell carcinoma. The survival rate of patients with adenocarcinoma was significantly higher than that of patients with
squamous cell carcinoma and that of patients with large
cell carcinoma. The 5-year survival rate (62%) of 63 patients with a T1 lung cancer was significantly higher
than the 5-year survival rate (32%) of 79 patients with
a T2 lung cancer, than the 4-year survival rate (23%) of
19 patients with a T3 lung cancer and the 4-year survival rate (15%) of 13 patients with a T4 lung cancer.
The 5-year survival rate (74%) of 86 patients with an
NO lung cancer was significantlyhigher than the 3-year
survival rate (190/) of 24 patients with an N 1 lung cancer, the 3-year survival rate (12%) of 54 patients with
an N2 lung cancer, and the 2-year survival rate (0%) of
10 patients with an N3 lung cancer. The 2-year survival
rate (6%) of 16 patients with an M1 lung cancer was
significantly lower than the 5-year survival rate (45%)
of 158 patients with an MO lung cancer. The 5-year survival rate (80%)of 73 patients with a Stage I lung cancer
was significantly higher than the 2-year survival rate
(530/0)of 15 patients with a Stage I1 lung cancer, the 2year survival rate (28%) of 70 patients with a Stage 111
lung cancer, and the 2-year survival rate (6%) of 16 patients with a Stage IV lung cancer.
Discussion
Patients with lung cancer included in this study were
found in a limited number of 46 local municipalities
during a limited period to reduce selection bias and to
determine the exact distribution of DT as much as possible. DT was found to have a log normal distribution
after logarithmic conversion in accordance with the results of other investigator^.'^-'^ Thus, it was justified to
analyze the data of DT by using geometric means,"
rather than the arithmetic means that had been used for
the analyses of DT of lung cancer.
The minimum size of lung cancer that can be detected on a chest X-ray film has been reported to be 6
mm,1,3,11 7 mm,19,20 8 mm ,21 or 1 cm.7,22~illington'
stated that, if prior chest films show no tumor, one can
calculate an upper limit doubling time by assuming that
a nodule was present and was only 8 mm in greatest
dimension (the lower margin of detectability) in the
most recent negative film. In our experience, detection
of lung cancer that is smaller than 6 mm has been impossible. Thus, DT was calculated under the presumption that a tumor was present and had a greatest dimension of 6 mm in the most recent negative film taken
within 1 year before the time when the tumor was de-
2243
Table 2. Results of Multivariate Analyses Using the Cox Proportional Hazard Model
X2
Variable
Beta
Standard error
(Chi-sauare)
P-value
N factor
0.7485
0.8132
0.9816
0.3736
-0.0022
-0.4961
0.1212
0.2583
0.3125
0.1194
0.0009
0.2762
38.12
0.0001
0.0016
0.0017
Therapy
M factor
T factor
DT
Sex
9.91
9.87
9.79
5.89
3.23
0.0018
0.0152
0.0724
N factor: regional lymph node factor; M factor: distant metastasis factor; I factor: primary tumor factor
tected for the first time. Not all of the areas on chest Xray are as sensitive. However, all of the patients included in our study had a tumor shadow that was easier
to detect in the peripheral lung field. Thus, our assumption is valid that the minimum size of lung cancer that
can be detected on a chest X-ray film is 6 mm. If the
rapidly growing tumors are excluded from the analysis,
the distribution of DT may shift to the range of longer
DT, so the population included for evaluation may not
reflect the actual pattern of distribution of DT. Thus,this
assumption is justified in the absence of other suitable
methods.
We have reported previously that the prognosis of
the patients with a rapidly growing lung cancer is worse
than that of patients with a slowly growing lung can~ e r ' , ' and
~ that an early peripheral lung cancer24is undetectable in its initial phase but remains in the early
stage because the growth rate is
Gomperzian
kineticsz6predicts that the more advanced the tumor,
the more slowly it is expected to grow. However, our
result showed that patients with disease detected at advanced stages were expected to have shorter DT and
patients with disease detected at early stages were expected to have longer DT. In our study, the mean of
DT was significantly shorter in men than in women; in
patients with a smoking history than in patients without
a smoking history; and in patients with symptoms than
in patients without symptoms. The mean DT in patients
with an adenocarcinoma was significantly longer than
that in patients with a squamous cell carcinoma and significantly longer than that of patients with an undifferentiated carcinoma. The mean DT in patients with a T1
lung cancer was significantly longer than that in patients with a T2, T3, or T4 lung cancer. The survival rate
in patients with a shorter DT was significantly lower
than that in those with a longer DT. A similar tendency
was observed for other prognostic factors. The prognosis of patients with a shorter DT has been reported to be
poor~Z-4,7,15,1 6.23.27-30
In addition, the results of our study
showed that, even when analyzed with reference to
each prognostic factor, the survival rate of patients with
a shorter DT was significantly lower than that of those
2244
Growth rate data help to differentiate between benign and malignant pulmonary nodules.31 Spratt and
Spratt31 reported that a tumor with a DT slower than
500 days usually was benign. In our study, 162 (93%)
of 174 patients had DT of 30-500 days, in contrast with
the data by Spratt and Spratt. In our study, GM (AM) of
DT in cell type was 163.3 days (223.1 days) for adenocarcinomas, 80.3 days (104.8 days) for squamous cell
carcinoma, 69.2 days (80.9 days) for small cell carcinomas, and 66.8 days (79.4 days) for large cell carcinomas.
Growth rate has been reported to be faster in squamous
cell carcinomas and undifferentiated carcinomas but
slower in a d e n o c a r c i n ~ m a s . ~Filderman
, ~ , ~ ~ ~ ~et
~ aL7 reported that the AM of DT was 180 days for adenocarcinomas, 100 days for squamous cell carcinomas and
large cell carcinomas, and 30 days for small cell carcinomas. Geddes4 compiled data from 228 patients for
whom DT were available in the literature and reported
that the AM of DT was 161 days for patients with adenocarcinomas, 88 days for those with squamous cell
carcinomas, 86 days for those with large cell carcinomas, and 29 days for those with small cell carcinomas.
According to Fujimura et
the AM of DT was 116
days for adenocarcinomas, 94 days for squamous cell
carcinomas, and 71 days for large and small cell carcinomas. This difference in mean DT may be attributable
to a difference in the protocols by which subjects for
evaluation were selected.
References
1. Spratt JS, Ter-Pogossian M, Long RTL. The detection and
growth of intrathoracic neoplasms. Archiv Surg 1963; 86:283-8.
2. Meyer JA. Growth rate versus prognosis in resected primary
bronchogenic carcinomas. Cancer 1973; 31:1468-72.
3. Weiss W. Tumor doubling time and survival of men with bronchogenic carcinoma. Chest 1974; 65:3-8.
4. Geddes DM. The natural history of lung cancer: a review based
on rates of tumour growth. BrJDis Chest 1979; 73:l-17.
5. Mizuno T, Masaoka A, Ichimura H, Shibata K, Tanaka H, Niwa
H. Comparison of actual survivorship after treatment with survivorship predicted by actual tumor-volume doubling time from
tumor diameter at first observation. Cancer 1984; 532716-20.
6. Heikkila L, Mattila P, Harjula A, Suomalainen RJ, Mattila S. Tumour growth rate and its relationship to prognosis in bronchioloalveolar and pulmonary adenocarcinoma. Ann Chir Gynaecof
1985; 74:210-4.
7. Filderman AE, Shaw C, Matthay RA. Lung cancer: Part I. Etiology, pathology, natural history, manifestations, and diagnostic
techniques. Invest Radiol 1986; 21230-90.
8. Usuda K, Saito Y, Takahashi S, Kanma K, Sagawa M, Sato M, et
al. Clinical study using previous miniature radiographs of lung
cancer cases detected during radiologic screening program. 1Jpn
Lung Cancer SOC 1990; 30:857-61.
9. Lillington GA. Management of solitary pulmonary nodules. In:
Bone RC, editor. Disease-a-Month. Littleton: Mosby-Year Book,
199 1970-3 18.
10. Schwartz M. A biomathematical approach to clinical tumor
growth. Cancer 1961; 14:1272-94.
11. Arai T, Shiobara J, Shiozawa M, Iwai K. Discussion of the problems of early detection of peripheral lung cancer from the standpoint of the growth rate and the size of the tumor at detection. ]
Jpn Lung Cancer SOC 1976; 16:7-13.
12. Cox DR. Regression models and life-tables. J R Stat Soc (B) 1972;
34:187-220.
13. The Japan Lung Cancer Society. General rules for clinical and
pathological record of lung cancer, ed. 3. Tokyo: Kanehara,
1987.
14. International Union Against Cancer. TNM classification of malignant tumors, ed. 4. Berlin: Springer-Verlag, 1987.
15. Spratt JS, Spratt TL. Rates of growth of pulmonary metastases
and host survival.Ann Surg 1964; 159:161-71.
16. Chahinian AP, Israel L. Rates and patterns of growth of lung
cancer. In: Israel L, Chahinian AP, editors. Lung cancer: natural
history, prognosis, and therapy. New York: Academic Press,
1976~63-79.
17. Charbit A, Malaise EP, Tubiana M. Relation between the pathological nature and the growth rate of human tumors. Eurf Cancer
1971; 7~307-15.
18. Tango T, Furukawa T. Medical statistics. Tokyo: Asakura Shoten, 1983.
19. Matsuda M, Horai T. A roentgen study of the small peripheral
lung cancer. J l p n Lung Cancer Soc 1971; 11:35-45.
20. Heelan RT, Flehinger BJ, Melamed MR, Zaman MB, Perchick
WB, Caravelli JF, et al. Non-small-cell lung cancer: results of the
New York screening program. Radiology 1984; 151289-93.
21. Steele JD, BueIl P. Asymptomatic solitary pulmonary nodules:
host survival, tumor size, and growth rate. 1Thor Cardiovasc Surg
1973; 65:140-51.
22. Straus MJ, Janis MG, Moran RE. Tumor biology of lung cancer.
In: Harris CC. Pathogenesis and therapy of lung cancer. New
York Marcel Dekker, 1978:611-51.
23. Usuda K, Saito Y, Sagawa M, Sat0 M, Nagamoto N, Fujimura S,
et al. Clinical and radiographic changes in relation to times of
screening and survival in lung cancer cases detected by the Miyagi screening program using annual chest radiographs. J Jpn
Lung Cancer SOC 1990; 30:483-90.
24. Ikegda S. Atlas of early cancer of major bronchi. Tokyo: Igaku
Shoin, 1976.
25. Usuda K, Takahashi 5, Kanma K, Ota 5, Imai T, Saito Y, et al.
Analysis of the diagnostic process and a retrospective study of
the Miyagi annual chest X-ray lung cancer screening program. J
Jpn Lung Cancer Soc 1988; 28:343-52.
26. Gompertz B. On the nature of the function expressive of the law
of human mortality, and on a new mode of determining the
value of life contingencies. Philos Trans R SOC 1825; 115:513-85.
27. Malaise EP, Chavaudra N, Charbit A, Tubiana M. Relationship
between the growth rate of human metastases, survival and
pathological type. EurJ Cancer 1974; 10:451-9.
28. Bone RC, Balk R. Staging of bronchogenic carcinoma. Chest
1982; 821473-80.
29. Joseph WL, Morton DL, Adkins PC. Prognostic significance of
tumor doubling time in evaluating operability in pulmonary
metastatic disease. 1Thorac Cardiovasc Surg 1971; 6123-32.
30. Collins VP, Loeffler RK, Tivey H. Observations on growth rates
of human tumors. Am J Roentgenof 1956; 76:988-1000.
31. Spratt JS, Spratt JA. The prognostic value of measuring the gross
linear radial growth of pulmonary metastases and primary pulmonary cancers. 1 Thorac Cardiovasc Surg 1976; 71274-8.
32. Weiss W. Peripheral measurable bronchogenic carcinoma. Am
Rev Respir Dis 1971; 103:198-208.
33. Fujimura S, Suda S, Yamauchi A, Sato H, Sohara Y, Kondo T, et
al. Tumor doubling time and PPD skin test reactivity in resectable lung cancer. J J p n Lung Cancer Soc 1979; 19:135-42.