Cancer Letters, 4 (1978) 311--316 © Elsevier]North-Holland Scientific Publishers Ltd.

311

ACTUAL VOLUME D O U B L I N G TIME VALUES F O R P U L M O N A R Y METASTASES F R O M S O F T TISSUE SARCOMAS

S. PLESNICAR, G. KLANJSCEK and SONJA MODIC

The Institute of Oncology and Faculty of Medicine, University of Ljubljana, Ljubljana (Yugoslavia) (Received 28 December 1977) (Revised version received 3 April 1978) (Accepted 3 April 1978)

SUMMARY

Doubling time values of pulmonary metastases from soft tissue sarcomas were measured. Sixty metastases from 24 patients were measured 79 consecutive times, and, the values for 116 doubling times were calculated. Small volume metastases grew significantly faster (arithmetic mean 29.7 days) than large metastases (arithmetic mean 43.4 days). An assessment with comparative data obtained previously by measuring the doubling time values of pulmonary metastases from osteogenic sarcoma revealed similar growth characteristics. The possible involvment of identical control mechanisms operating in the growth process of pulmonary metastases in both soft tissues and osteogenic sarcomas are discussed.

INTRODUCTION

The soft tissue sarcomas represent a heterogenous group o f mostly fast growing tumors, which originate from the mesoderm and have in c o m m o n an inherent tendency to metastasise predominantly to the lung. A recent report indicates [9] that the use of combination chemotherapy produces various degrees of regression of pulmonary metastases. In all instances a proper evaluation ,of the therapeutic effects could be achieved only if detailed knowledge a b o u t growth rates of pulmonary metastases was at hand. So far, for such purposes a quantification of the growth rates by,determination of t u m o r doubling time has been utilized [1]. The mean value for doubling time in soft

Address correspondence to : S. Plesni~ar, M.D., The Institute of Oncology and Faculty of Medicine, Vrazov trg 4, 61000 Ljubljana, Yugoslavia.

312

tissue sarcoma pulmonary metastases was reported to be 85.6 days [2]. This value was calculated by .using for doubling time 23 values obtained by measuring pulmonary metastases only once, that is in a series of 23 patients. In 5 of the 23 instances studied the value for doubling time of pulmonary metastases was calculated to be over 100 days. Also the range of values reported for doubling time appeared to be extremely large, extending from 10 days to over 340 days [5]. Since it is possible that the growth rate of pulmonary metastases could relate directly to their volume, additional information regarding these parameters was thought to be helpful. The present investigation deals with the study of doubling time values for pulmonary metastases from soft tissue sarcomas grouped according to their volume. The basic statistical data (e.g., the arithmetic mean, standard deviation and standard error) were calculated, using the same criteria as employed in our previous study [6] for osteogenic sarcoma. MATERIAL AND METHODS

This report concerns a retrospective study from chest radiograms of 24 patients with histologically proven soft tissue sarcomas. Among these patients, the diagnosis of fibrosarcoma was found in 15 cases; rhabdomyosarcoma was diagnosed in 5 cases; and the remaining 4 cases included histologically confirmed diagnoses of one each leiomyosarcoma, liposarcoma, hemangioperic y t o m a and angiosarcoma. The age of patients ranged from 31 to 90 years; four patients were over 80 years old. No antitumor therapy was given to the patients during the observation period. In all instances sharply distinct and predominately spherical shaped metastatic growths were selected for measurement. Altogether 60 metastases were measured on 79 consecutive dates, and 116 values for doubling time were calculat.ed. One value for doubling time was obtained for 27 metastatic growths, 2 values for 26 metastatic growths, 3 values for 6 metastatic growths, 6 values for 2, and 7 values for 1 metastatic growth. The largest metastatic growth had a diameter of 120 mm. The values for doubling time were calculated according to the method described by Collins [3] and by using the values for calculated doubles related to the changing diameter reported by Twardzik and Sklaroff [8]. The values were subsequently tested b y statistical methods; and the arithmetic mean, standard deviation and the standard error were determined. The correlation coefficients were calculated among different parameters and tested for significance. Also the difference among arithmetic means were statistically tested for significance. RESULTS

The arithmetic mean for all 116 doubling times calculated was 69.9 days (1 S.D. = +84.6 days; S.E. = 7.9 days) (Table 1). The observation time period covered 365.9 days (4.7 days to 370.6 days). Among the original 116 doubling

a b c d

3 . 0 - - 6.9 7 . 0 - - 9.9 1 0 . 0 - - 14.9 3 . 0 - - 14.9 1 5 . 0 - - 19.9 2 0 . 0 - - 29.9 3 0 . 0 - - 39.9 4 0 . 0 - - 59.9 60.0--111.0 15.0--111.0 3.0--111.0 100 - - 3 7 0 . 6 3.0--111.0

2

Diameter of metastases (mm)

11 9 20 40 15 19 6 9 5 54 94 22 116

3

Number of doubling times times (n)

4.82 8.22 11.70 9.03 17.20 22.84 32.33 47.22 80.80 31.76 22.09 31.50 23.87

4 15.13 35.80 35.29 29.66 42.94 42.18 51.80 43.81 38.80 43.42 37.65 207.55 69.87

5 1.25 0.97 1.49 3.24 1.92 2.50 2.42 7.56 20.56 19.99 18.97 19.01 19.25

6

Dia (ram)

Dia a (mm)

Dt b (days)

Standard deviation (S.D.)

Arithmetic mean (K)

13.10 22.35 15.95 18.84 32.92 25.93 24.67 22.10 30.23 26.93 24.6 109.72 84.64

7

Dt (days)

0.38 0.32 0.33 0.51 0.34 0.57 0.99 2.52 9.19 2.72 1.96 4.05 1.79

8

Dia (mm)

Range (R)

3.95 7.45 3.57 2.96 8.50 5.95 10.07 7.37 13.22 3.66 2.54 23.39 7.86

9

3.00 2.00 4.00 11.00 4.00 8.00 6.00 18.00 51.00 96.00 108.00 60.00 108.00

10

Dt Dia (days) ( m m )

Standard error (S.E.)

Dia, D i a m e t e r Dt, D o u b l i n g t i m e In g r o u p n u m b e r 9 ( c o n s e c u t i v e n u m b e r 1 2 ) m e t a s t a s e s w i t h d o u b l i n g t i m e s o f over 1 0 0 days are g r o u p e d . T h e u n d e r l i n e d c o e f f i c i e n t s of c o r r e l a t i o n are s t a t i s t i c a l l y s i g n i f i c a n t (P ~< 0 . 0 5 0 ) .

1 2 3 e(1--3) 4 5 6 7 8 e(4--8) e(1--8) 9 c Dt e(1--9)

1

0

1 2 3 4 5 6 7 8 9 10 11 12 13

Group number

Consecutive number

44.10 63.30 55.40 61.10 80.80 61.00 64.80 59.60 70.20 87.10 87.80 267.60 365.90

11

Dt (days)

+0.17 -0.14 +0.05 +0.40 d -0.05 +0.13 -0.04 -0.06 +0.25 -0.00 +0.18 +0.05 +0.21 d

12

Coefficient of correlation (r)

S T A T I S T I C A L A N A L Y S I S O F 116 D O U B L I N G T I M E S O F P U L M O N A R Y M E T A S T A S E S F R O M S O F T T I S S U E S A R C O M A S

TABLE 1

314

time values there were 22 doubling time values (18.9% of all observations) that ran over 100 days. These were excluded f r om the final evaluation due to their influence on the value of the arithmetic mean parameter. The arithmetic mean for the 94 doubling time values (81% of all measurements) was 37.7 days (1 S.D. = +24.7 days; S.E. = 2.5 days). The observation period was 87.8 days. The minimal value was 4.7 days and the maximal value, 92.5 days. The 94 values for doubling time that were studied in relation to the size range of the met~stase showing the following parameters: Small metastases with diameters up to 14.9 mm had an arithmetic mean for doubling time of 29.7 days (1 S.D. = -+18.8 days; S.E. = 3.0 days), whereas metastatic growths with diameters that ranged f r o m 15.0 m m to 111.0 mm had a substantially higher arithmetic mean for doubling time, t ha t is 43.4 days (1 S.D. = -+26.9 days; S.E. = 3.7 days). The difference between the arithmetic means for small and large metastases was statistically significant (P ~< 0.050). From the data obtained in this series it is evident that as the size of metastatic growths increase, the values for doubling times also increase. Therefore, it appears t hat the slowing of the growth rates of p u l m o n a r y metastases for soft tissue sarcoma is probably size dependent. In the group o f values for doubling time over 100 days, which included 22 observations, the arithmetic mean was 207.6 days (1 S.D. = -+109.7 days; S.E. =

TABLE 2 C O M P A R I S O N OF G R O W T H C H A R A C T E R I S T I C S OF P U L M O N A R Y M E T A S T A S E S IN P A T I E N T S WITH S O F T T I S S U E S A R C O M A S AND O S T E O G E N I C S A R C O M A Consecutive number

Number of doubling times

Diameter of metastases (mm)

Doubling t i m e values Arithmetic mean ± 1 Standard deviation (days)

I. S o f t tissue sarcomas 1 116 2 22 (18.9%) 3 94 4 40 5 54

3.0--111.0 Dt : 100 - - 3 7 0 days 3.0--111.0 3 . 0 - - 14.9 15.0--111.0

69.87 267.55 37.65 29.66 43.42

± 84.64 ± 109.72 ± 24.65 ± 18.84 ± 26.93

II. Osteogenic sarcoma 1 126 2 13 (10.3%) 3 113 4 78 5 35

3.0--135.5 Dt : 100 - - 2 1 2 days 3.0--135.5 3 . 0 - - 19.9 20.0--135.5

41.08 136.08 30.16 27.0S 37.03

+ + ± ± ±

Significance o f d i f f e r e n c e s : B e t w e e n g r o u p I/1 a n d g r o u p B e t w e e n g r o u p I/3 a n d g r o u p B e t w e e n g r o u p I/4 a n d g r o u p B e t w e e n group I/5 and group

II/l: P = II/3 : P = II/4: n o t II/5 : n o t

0.001. 0.05. significant. significant.

38.32 34.15 18.62 16.54 21.40

315 23.4 days). The observation period range was 267.6 days, with a minimal value of 103.0 days and a maximal value of 370.6 days. The calculated data for pulmonary metastases from soft tissue sarcomas are summarized in Table 2. For comparison purposes the identical values for osteogenic sarcoma p u l m o n a r y metastases, as reported previously [6], are also included. As can be seen the doubling time values for pulmonary metastases from soft tissue sarcomas had a considerably higher arithmetic mean value (69.9 days) than t h a t f o u n d in the osteogenic sarcomas (41.1 days). The difference between these values is clearly significant (P ~< 0.001). This relatively higher arithmetic mean value for the doubling time of the soft tissue sarcomas over osteogenic sarcomas series, however, is influenced by the inclusion of a greater percentage of doubling time values (18.9% of all observations) running over 100 days in the soft tissue sarcomas series. When the values for doubling time running for over 100 days were excluded, the calculated arithmetic mean values for both groups were considerably shorter, t h a t is 37.7 days for soft tissue sarcoma series and 30.2 days for osteogenic sarcoma series. The arithmetic means for doubling time calculated for small metastases were similar for both types of neoplasms. The values for the arithmetic mean for pulmonary metastases from soft tissue sarcomas was 29.7 days, and for pulmonary metastases from osteogenic sarcoma, 27.1 days. A similar tendency was observed in large metastases where the arithmetic mean for doubling time for soft tissue sarcomas was 43.4 days, and in osteogenic sarcoma pulmonary metastases was 37.0 days. In both instances the difference between values was not statistically significant (P t> 0.05). DISCUSSION The possibility that sarcomas originating in various tissues and organs may exhibit different growth characteristics, both at the site of origin and as metastatic growths, should be rationally considered, particularly when managing the t r e a t m e n t of these neoplastic tumors [4,7]. The data from this investigation indicate that pulmonary metastases of sarcomas originating from soft tissue had a high arithmetic mean value for doubling time (69.9 days), when all metastatic growths from the series were considered. The exclusion of metastatic growth t h a t ran the doubling time over 100 days, however, substantially lowered the arithmetic mean value (37.7 days). It is of interest that similar or almest identical values for these parameters have been recorded for pulmonary metastase s originating from osteogenic sarcomas [ 6 ]. For example, the doubling times for small pulmonary metastases of soft tissue sarcomas had an arithmetic mean value of 29.7 days, and the arithmetic mean for pulmonary metastases of osteogenic sarcomas was 27.1 days. A somewhat higher, but statistically n o t significant difference, was also observed between the arithmetic mean values of doubling time for large metastases (43.4 days) of soft tissue sarcomas and p u l m o n a r y metastases of osteogenic sarcomas (37.0 days). Clearly, the comparison of these data indicates also a similarity in growth trend patterns for

316 b o t h t y p e s o f p u l m o n a r y m e t a s t a s e s . A t e n d e n c y t o r a p i d g r o w t h o f small m e t a s t a t i c g r o w t h s in b o t h s o f t tissue a n d o s t e o g e n i c s a r c o m a was o b s e r v e d . By c o n t r a s t in b o t h i n s t a n c e s t h e large sized m e t a s t a t i c g r o w t h s e x h i b i t e d s u b s t a n tially s l o w e r g r o w t h rates. T h e r e t a r d a t i o n o f g r o w t h s in large m e t a s t a s e s can be a t t r i b u t e d t o a n u m b e r o f biological f a c t o r s a m o n g w h i c h the e x t e n t o f necrosis w i t h i n the n e o p l a s t i c tissue m a y p l a y a significant role. A c c o r d i n g t o t h e s e o b s e r v a t i o n s , t h e e s t a b l i s h e d basic characteristics o f g r o w t h in t h e s e series a p p e a r t o be similar, a n d it m a y be c o n c l u d e d t h a t t h e m e c h a n i s m g o v e r n i n g t h e g r o w t h rates o f p u l m o n a r y m e t a s t a s e s are p r o b a b l y i d e n t i c a l f o r m e t a s t a t i c g r o w t h s originating f r o m s o f t tissue s a r c o m a s and t h o s e f r o m o s t e o g e n i c s a r c o m a s . A similar m e c h a n i s m g o v e r n i n g t h e m e t a s t a t i c g r o w t h m a y b e involved also in t h e n e o p l a s m s originating f r o m epithelial tissues since it is k n o w n t h a t large size p u l m o n a r y m e t a s t a s e s f r o m e p i d e r m o i d a n d o t h e r c a r c i n o m a s m a n i f e s t e x t e n s i v e necrosis. REFERENCES 1 Band, P.R. and Kocandrle, C. (1975) Growth rate of pulmonary metastases in human sarcomas. Cancer, 36,471--474. 2 Breuk, K. (1966) Growth rate and radiosensitivity of human tumours -- I. Growth rate of human tumours. Eur. J. Cancer, 2,157--171. 3 Collins, V.P., Loftier, R.K. and Tivey, H. (1956) Observations on growth rates of human tumors. Am. J. Roentgenol., 78,988--1000. 4 Jaffe, N. (1975) The potential of combined modality approaches for the treatment of malignant bone tumors in children. Cancer Treat. Rev., 2, 33--53. 5 Joseph, W.L. (1974) Criteria for resection of sarcoma metastatic to the lung. Cancer Chemother. Rep. (Part 1), 58,285--290. 6 Plesni~ar, S., Klanj~ek, G., Modic Sonja and Habit, M. (1976) The significance of doubling time values in patients with pulmonary metastases of osteogenic sarcoma. Cancer Letters, 1,351--358. 7 Rosen, G., Tefft, M., Martinez, A., Chain, W. and Murphy, M.L. (1975) Combination chemotherapy and radiation therapy in the treatment of metastatic osteogenic sarcoma. Cancer, 35,622--630. 8 Twardzik, F.G. and Sklaroff, D.M. (1976) Growth analysis of pulmonary metastases from salivary gland tumors. Am. J. R0entgenol. , 126, 493--499. 9 Wilbur, J.R., Sutow, W.W., Sullivan, M.P. and Gottlieb, J.A. (1975) Chemotherapy of sarcomas. Cancer, 36, 765--769.

Actual volume doubling time values for pulmonary metastases from soft tissue sarcomas.

Cancer Letters, 4 (1978) 311--316 © Elsevier]North-Holland Scientific Publishers Ltd. 311 ACTUAL VOLUME D O U B L I N G TIME VALUES F O R P U L M O...
354KB Sizes 0 Downloads 0 Views