Tumor Doubling Time

2239

Tumor Doubling Time and Prognostic Assessment of Patients with Primary Lung Cancer Katsuo Usuda, M.D., Yasuki Saito, M.D., Motoyasu Sagawa, M.D., Masami Sato, M.D., Keiji Kanma, M.D., Satomi Takahashi, M.D., Chiaki Endo, M.D., Yan Chen, M.D., Akira Sakurada, M.D., and Shigefumi Fujimura, M.D.

Background. Relationships between tumor doubling time (DT) and other prognostic factors and the risk of death related to these factors are not yet fully understood.

Methods. Tumor doubling time of primary lung carcinomas of 174 patients, detected in a limited number of local municipalities during a limited period, was calculated using the Schwartz formula. Survival rate of the 174 patients was compared with reference to categories of prognostic factors (univariate analyses) and significant factors affecting survival were identified by multivariate analyses using the Cox proportional hazard model.

Results. Tumor doubling time had a log normal distribution. There was a significant difference in mean DT in relation to sex, smoking history, presence of symptoms, cell type, primary tumor factor, and stage. Univari- ate analyses showed a significant difference in survival in relation to DT, age, sex, method of tumor detection, smoking history, symptoms, therapy, cell type, primary tumor (T) factor, regional lymph node (N) factor, distant metastasis (M) factor, and stage. Multivariate analyses using the Cox's proportional hazard model in a stepwise fashion identified a final set of five significant variables: N factor (P = 0.0001); therapy (P = 0.0016); M factor (P = 0.0017); T factor ( P = 0.0018), and DT ( P = 0.0152).

Conclusions. Tumor doubling time was an independent and significant prognostic factor for lung cancer patients. Cancer 1994; 742239-44.

Key words: primary lung cancer, growth rate, tumor doubling time, prognostic factor, survival rate, multivariate analysis, Cox proportional hazard model.

From the Department of Thoracic Surgery, Institute of Develop-

Supported in part by a grant-in-aid for cancer research from the

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, To- hoku 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.

ment, Aging and Cancer, Tohoku University, Sendai, Japan.

Japanese Ministry of Health and Welfare (2-4).

The growth rate of cancer, which reflects the degree of malignancy, is closely related to prognosis. There have been numerous reports on the growth rate of primary lung cancer.'-9 However, relationships between the growth rate of cancer and other prognostic factors are not fully understood. In the current study, tumor doubling time (DT) was calculated for primary lung cancers that were detected in a limited number of local municipalities during a limited period. Survival rate was compared in relation to the categories of prognostic factors; in addition, multivariate analyses were used to evaluate the risk of death related to DT and other prognostic factors.

Patients and Methods

The subjects of the current study were 174 patients (123 men and 51 women) in 46 local municipalities during the period from January 1985 to December 1986. These were the only patients who had chest X-rays taken between 3-12 months before detection of lung cancer. There was no selection. Seven patients with a central tumor were excluded because of postatelectatic changes that precluded measurements. All of the patients in our study had a tumor shadow that was easier to detect in the peripheral lung field. The age of patients ranged from 33 to 86 years (mean, 67 years). Of the 174 patients, 129 had disease detected by the annual lung cancer screening trial in Miyagi Prefecture. Forty-five had disease detected in the Hospital attached to the Institute of Development, Aging and Cancer, Tohoku Univer- sity, Sendai Kousei Hospital, or Miyagi Prefectural Semine Hospital, where they reported symptoms or were treated for other diseases. One hundred twenty- six patients with lung cancer underwent resection, and 48 underwent nonsurgcal treatment. Thirty-three received chemotherapy or radiotherapy. No treatment was given to 15 patients. There were 86 adenocarcinomas, 67 squamous cell carcinomas, 7 small cell carcino-

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shadow of tumor

Figure 1. Calculation of tumor doubling time (DT). t: time between the initial and second measurement; V,: tumor volume at the initial measurement; a,: maximum dimension of tumor at the initial measurement; b,: perpendicular dimension of tumor that crosses a, at the midpoint; V,: tumor volume at the second measurement; a,: maximum dimension of tumor at the second measurement; b,: perpendicular dimension of tumor that crosses a, at the midpoint.

mas, 12 large cell carcinomas, 1 carcinoid, and 1 adeno- squamous carcinoma. Of the 126 patients with resected lung cancer, 2 had a Stage I localized bronchioloal- veolar carcinoma and 1 had a Stage I11 bronchioloal- veolar carcinoma. In 48 patients who underwent nonsurgical treatment, diagnosis was made by cytology, and the number of patients with a localized bronchio- loalveolar 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 pos- teroanterior 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 pa- thologist 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 3- 12 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 Prefec- ture, 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-

ease detected by hospital X-rays, and 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 hospital X-rays was 11 months. There was no difference in the mean time interval between the last normal chest X-ray and the abnormal chest X-ray in the patients with disease detected by screening as op- posed to the patients with disease detected by hospital X-rays.

As of June 1991, 64 of the 174 patients were alive, 99 were dead of lung cancer, and 11 were dead of diseases other than cancer.

Survival rates were compared in relation to categories of prognostic factors (univariate analyses), and an attempt was made to evaluate the risk of death related to DT and other prognostic factors by multivariate analyses using the Cox proportional hazard model."

Tumor histologic type and stage were documented based on the criteria of clinical and pathologic records of lung cancer of the Japan Lung Cancer Society,13 which essentially is the same as that of the International Union Against Cancer (UICC) clas~ification.'~ Data of measurement were documented in terms of arithmetic mean k standard deviation (AM k SD) or in terms of geometric mean (GM). The significance of difference in mean value was checked by the Wilcoxon rank sum test, and the significance of difference in ratio by the chi- square test. Survival rates were calculated by the Kaplan-Meier method. In this calculation, deaths attributable to diseases other than recurrence of lung cancer were excluded. Statistical evaluation in relation to categories of prognostic factors was done with the log rank test. The level of statistical significance was set at P < 0.05.

Results

Distribution of DT of Lung Cancer

The minimum DT was 30 days, and the maximum DT was 1077 days. DT after logarithmic conversion is shown in Figure 2. Both skewness (0.7204) and kurtosis (-0.0643) are small. Thus, DT was found to have a log normal distribution (AM f SD of DT was 163.7 f 177.5 days, and GM was 113.3 days). The mean of DT of each category of prognostic factors in terms of AM +- SD and GM are shown in Table 1.

Comparison of Survival Rate in Relation to Categories in Prognostic Factors (Univariate Analyses)

DT, the distribution of which is log normal, was classified into two groups with reference to GM (113.3 days). Tumors with a DT of less than 113.3 days were grouped

Tumor Doubling Time of Primary Lung CancerjUsuda et al. 2241

30L

1.5 2.0 2.5 3.0 LcglOScale (31.6) (1 00) (31 6) (1 000) (days)

Log (DT) Figure 2. Distribution after logarithmic conversion of DT. Skewness: 0.7204; kurtosis: -0.0643.

as rapidly growing tumors, and those with a DT of more than 113.3 days as slowly growing tumors. The 5-year survival rate (29%) of 98 patients with a rapidly growing tumors was significantly lower than that (55%) of 76 patients with slowly growing tumors (Fig. 3).

All of the patients of this study were classified into two groups with reference to the mean age (67 years). The 5-year survival rate (48%) of 82 patients who were 67 years or younger was significantly higher than that (33%) of 92 patients who were older than 67 years. The 5-year survival rate (32%) of 123 men was significantly lower than that @go/,) of 51 women. The 5-year survival rate (30%) of 45 patients with disease detected in a hospital was significantly lower than that (44%) of 129 patients with disease detected by the screening trial. The 5-year survival rate (35%) of 101 patients with a smoking history was significantly lower than that (48%) of 73 patients without a smoking history. The 5-year survival rate (30%) of 85 patients with symptoms was

Table 1. Mean Tumor Doubling Time in Relation to Prognostic Factors

Mean DT (days) Prognostic factor Category A M Z S D GM

Sex

Detection

Smoking history

Symptoms

Therapy

Cell type

T factor

N factor

M factor

Stage

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 MO M1 I II I11 Iv

(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 = 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)

(n = 7)

126.4 t 133.5 3 s 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

I* IS

104.7 2 105.6 80.8 t 49.7 79.4 * 51.9

145.6 ? 177.8 139.0 Z 193.7

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 1 118.6 t 76.7 125.7 -t 129.4 148.5 2 202.4

186.0 112.4 115.9

161.1

142.4 118.2 101.5

69.2 66.8

89.4

132.8 93.7 99.4 93.2

115.0 98.3

144.3 t 100.3 93.4 98.3

1 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 metastasis factor. * P < 0.001. i P < 0.01. $ P < 0.05.

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1%) iO0' .b

1 80

(n=76)

Rapidly-growing (DT< 11 3.3 days) (n=98)

1 _I pco.001

i h i 4 5 6

Years after diagnosis

Figure 3. Survival rate of patients with lung cancer as classified by growth rate.

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 significantly higher 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 2- year 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.

Multivariate Analyses Using the Cox Proportional Hazard Model Ten prognostic variables with reference to which survival rate was compared as described were classified as

follows: DT, continuous; age, continuous; sex (men = 0, women = 1); detection (detected by the screening trial = 0, detected when seen in hospital = 1); smoking history (without = 0, with = 1); symptoms (without = 0, with = 1); therapy (resection = 0, nonsurgical treatment = 1); primary tumor (T) factor (T1 = 0, T2 = 1, T3 = 2, T4 = 3); regional lymph node (N) factor (NO = 0, N1 = 1, N2 = 2, N3 = 3) and distant metastasis (M) factor (MO = 0, M1 = 1).

The risk of death related to DT and other prognostic factors was evaluated by multivariate analyses using the Cox proportional hazard model. A final set of five significant variables was obtained in a stepwise fashion (Table 2): N factor (P = 0.0001); therapy (P = 0.0016); M factor (P = 0,0017); T factor (P = 0.0018); and DT (P = 0.0152). The correlation coefficient was -0.193 between DT and N factor; -0.107 between DT and therapy; -0.027 between DT and M factor; and -0.134 between DT and T factor. As suggested by these small correlation coefficients, DT is an independent and significant prognostic factor of lung cancer. However, it was found that sex was not a significant factor (P = 0.0724).

The results of univariate analyses showed a significant dlfference in survival rates in relation to age, sex, detection (how a tumor was detected), smoking history, and symptoms. But the results of multivariate analyses showed that these five categories of prognostic factor were not significant.

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

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 im- possible. Thus, DT was calculated under the presump- tion 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-

mm,1,3,11 7 mm,19,20 8 mm , 21 or 1 cm.7,22 ~illington'

Tumor Doubling Time of Primary Lung Cancer/Usuda et al. 2243

Table 2. Results of Multivariate Analyses Using the Cox Proportional Hazard Model

Variable Beta Standard error X2

(Chi-sauare) P-value

N factor Therapy M factor T factor DT Sex

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 9.91 9.87 9.79 5.89 3.23

0.0001 0.0016 0.0017 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 X- ray 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- ~er ' , '~ and that an early peripheral lung cancer24 is un- detectable in its initial phase but remains in the early stage because the growth rate is Gomperzian kineticsz6 predicts 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

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

poor~Z-4,7,15,1 6.23.27-30

with a longer DT. Thus, it was found that DT is closely related to survival rate.

Univariate analyses showed significant differences in survival in relation to DT, age, sex, detection (how a tumor was detected), smoking history, symptoms, therapy, cell type, T factor, N factor, M factor, and stage, but it is unclear which factors affect the survival rate most strongly. In fact, there have been few publications on the influence of DT on survival rate with reference to TNM classification or prognostic factors other than TNM classification. In multivariate analyses using the Cox proportional hazard model for 10 factors (DT, age, sex, detection, smoking history, symptom, therapy, T factor, N factor, and M factor), five significant factors affecting survival were selected in a stepwise fashion in the increasing order as follows: N factor (P = O.OOOl), therapy (P = 0.0016), M factor (P = 0.0017), T factor (P = 0.0018), and DT (P = 0.0152). The correlation coefficient was -0,193 between DT and N factor, -0.107 between DT and therapy, -0.027 between DT and M factor, and -0.134 between DT and T factor. These four correlation coefficients being small shows that DT is an independent prognostic factor. TNM classification is useful for the accurate estimation of prognosis. Thus, a combination of DT and TNM classification is even more useful for the same purpose.

The survival rate of patients with disease detected in a hospital was significantly lower than that of patients with disease detected by the screening trial, and the results of multivariate analyses showed that the factor of detection was not significant. These data may sug- gest length bias in cancer screening. The survival rate of men was significantly lower than that of women, and the results of multivariate analyses showed that the factor of sex was not significant. A correlation was found between sex and other prognostic factors. Better SUP vival in women was associated with long DT, not smoking, NO, resection, and absence of symptoms. Factors of age, smoking history, and symptoms were significantly correlated with survival when they were analyzed by univariate analyses, but multivariate analyses showed that they were not significantly correlated.

2244 CANCER October 15,1994, Volume 74, No. 8

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 adenocarcin~mas.~,~,~~~~~ 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.

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