a new parameter for measuring metastatic bone involvement ...a new parameter for measuring...

Vol. 4, 1765-1772, July 1998 Clinical Cancer Research 1765

A New Parameter for Measuring Metastatic Bone Involvement by

Prostate Cancer: The Bone Scan Index’

Massimo Imbriaco, Steven M. Larson,2

Henry W. Yeung, Osama R. Mawlawi,

Yusuf Erdi, Ennpadam S. Venkatraman, and

Howard I. ScherNuclear Medicine Service [M. I., S. M. L., H. W. Y., 0. R. M.,

H. I. S.], Department of Medicine, Genitourinary Oncology Service[H. I. S.], Department of Medical Physics tY. E.], and Department ofBiostatistics and Epidemiology [E. S. V.], Memorial Sloan-KetteringCancer Center, New York, New York 10021

ABSTRACTIn this report, we describe a method for quantitative

bone scan interpretation (the Bone Scan Index or BSI) in

advanced prostate cancer. The BSI estimates the fraction of

the skeleton that is involved by tumor, as well as the regional

distribution of the metastases in the bones. The purpose of

this report is to describe the development and validation of

this method in terms of reproducibility and the application

of BSI for determining extent of disease and monitoring

disease progression. We analyzed 263 bone scans from 90

patients being studied under four protocols at Memorial

Sloan-Kettering Cancer Center for progressive, androgen-

independent prostate cancer (AIPC), who had bone scans as

a part of their work-up. We determined: (a) the intraob-

server and interobserver variability of the BSI; (b) the com-

parison between a change in BSI and prostate-specific anti-

gen (PSA); (c) the regional distribution of bony metastases

in early stage D prostate cancer (<3% skeletal involve-

ment); and (‘0 the rate of growth of bony metastases from

prostate cancer. A cube root transformation of the percent-

age of involvement of the entire skeleton was used to stabi-

lize the variance over the entire span of values (0-60%

tumor involvement). The range of interobserver variability

between readers was 0.2-0.5 times the cube root of the BSI

(69 scans, 18 patients). Intraobserver variability was mini-

mid when the same reader read the same scans after a 2-year

interval, showing a correlation coefficient of 0.97 (reader 1)

and 0.99 (reader 2), P < 0.001. There was a parallel rise in

the BSI and the PSA in 24 patients (105 scans) treated for

AIPC with hydrocortisone followed by suramin at PSA

Received 1/6/98; revised 3/27/98; accepted 4/10/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact.I Supported in part by the Pepsico Foundation.

2 To whom requests for reprints should be addressed, at Nuclear Med-icine Service, Memorial Sloan-Kettering Cancer Center, 1 275 York

Avenue, New York, NY 10021. Phone: (212) 639-7373; Fax: (212) 717-3263: E-mail: [email protected].

relapse (Pearson’s moment correlation, 0.71). In a group of

27 patients with limited bone involvement by AIPC (i.e.,

<3% BSI), the distribution of early metastases was not

random within the skeleton but was distributed in the cen-

tral skeleton in a manner that matched the distribution of

the normal adult bone marrow. Also, in a group of 21

patients (62 scans), the change in BSI as a function of time

after diagnosis was explored graphically. The progression of

bone scan changes in AIPC, from early involvement (<3%)

to late involvement, was fitted to a Gompertzian equation. It

showed a rapid exponential growth phase, with an estimated

tumor doubling time of 43 days when the BSI was 3.3%. The

change in BSI rapidly approached a more gradual slope as the

percentage ofskeletal involvement increased. The BSI provides

a reproducible new parameter for quantitative assessment of

bone involvement by AIPC. These resnits suggest that the BSI

will be useful for stratifying patients entering treatment pro-

tocols for extent of tumor involvement of bone. Although fur-

ther study is necessary, serial bone scan BSI appears capable of

quantifying both the progression of bony involvement by tu-

mor as well as the response to treatment.

INTRODUCTIONProstate cancer has a tendency to spread to the bones, and

up to 80% of patients who die from prostate cancer have bone

metastases as a result of vascular spread and systemic dissem-

ination. Bone scintigraphy is an effective modality in the detec-

tion of skeletal metastasis, frequently providing the first evi-

dence of distant malignant spread. For example, the bone scan

has proven to be more sensitive than standard radiographic meth-

ods for detecting the initial spread of prostate cancer to bone (1).

Modern bone scanning uses a gamma camera and a Tc-

99m bone-seeking agent, usually methylene diphosphonate. An

area of increased uptake (“hot spot”) develops at the site of

metastatic involvement in bone because bone turnover is accel-

erated near the metastatic site and the scanning agent is incor-

porated into the bone mineral matrix in this region based on

accelerated bone mineral turnover. Modern bone scan tech-

niques can detect an increase in bone mineral turnover as small

as 10% in regions that are only a few millimeters in size. In

contrast, a relatively large volume of bone (- 1 cm3) must

demineralize by about 50% before the change can be detected

by plain radiographs (2). It is not surprising then, that in regard

to prostate cancer, the bone scan is often used to stage patients

and monitor the course of bony involvement. Improvements in

instrumentation, such as dual-headed gamma cameras that are

capable of whole-body scanning, have made rapid staging ex-

aminations convenient so that the entire skeleton can be sur-

veyed in less than 15 mm. The same instrument can also

perform single-photon emission computed tomography. Single-

photon emission computed tomography significantly increases the

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1766 BSI in Cancer of the Prostate

sensitivity of bone scanning for detecting metastases, especially in

the spine, which is a frequent site of initial metastatic involvement.

As a rule of thumb, if the patient is to have localized

treatment for prostate cancer, such as external beam radiation

therapy, a bone scan is performed to rule out metastatic involve-

ment of bone (3), especially in patients with a high Gleason’s

score and a PSA3 > 10 ng/ml (4).

As therapies improve for bone metastases of prostate can-

cer, better diagnostic methods are needed to more accurately

determine the amount of tumor present at baseline and to mon-

itor the tumor’s response to therapy. In contrast to the important

role of bone scans in the detection of tumor involvement of

bone, the present use of bone scintigraphy as a way to monitor

treatment response in prostate cancer is not optimal. In part this

reflects an inherent limitation of bone scintigraphy, which is that

the tumor is not directly visualized but only indirectly, because

it is the reaction of the bone to the local invasion by tumor that

is visualized. Other forms of damage to bone, such as degener-

ation or trauma, can also cause a positive bone scan. Also,

standard methods of bone scan interpretation are most corn-

monly descriptive in that nuclear medicine physicians usually

report a simple record of the detected sites of tumor in bones.

This method is appropriate for detecting tumor spread to bone

but is more difficult to use in monitoring tumor response be-

cause it is subjective and nonquantitative. The flare phenomena

(5), in which the healing bone becomes strongly positive in the

region of a tumor site that is responding to therapy, may delay

the diagnosis of a favorable treatment response. Interpretation is

difficult because the healing bone can show an increase in

intensity that mimics metastatic involvement. For this reason,

clinical information about the treatment status of the patient as

well as the PSA level is essential for proper interpretation of

changes in the scintigraphic pattern during therapy.

To improve the monitoring of the treatment of bone le-

sions, some authors have developed scoring systems for more

objective methods of assessing extent of bone metastases, such

as counting the number of lesions in the total skeleton and assessing

the regional distribution of the metastases (6). These methods are

difficult to apply to the problem of monitoring response to treat-

ment. In part this is because bone lesion counting methods become

tedious in advanced disease, and once the lesions become large and

coalesce, lesion counting may become impossible.

PSA has been shown to be of clinical value in monitoring

patients with prostate cancer who have undergone radical pros-

tatectomy, radiation therapy, and/or hormonal treatment (7-9).

Although PSA is probably the best current means for monitoring

tumor response and progression, this test also has limitations in

monitoring tumor response in bone. Although helpful in detect-

ing tumor and for showing progression, PSA levels do not

correlate in absolute terms with the tumor burden, and for a

given tumor size, the PSA value varies widely from patient to

patient. More poorly differentiated tumors produce less PSA per

gram than do well-differentiated tumors, and serum levels in a

3 The abbreviations used are: PSA, prostate-specific antigen; BSI, BoneScan Index: AIPC, androgen-independent prostate cancer; MSKCC,Memorial Sloan-Kettering Cancer Center.

given patient may also be influenced by the amount of benign

prostatic hypertrophy in residual prostate tissue. Also, for more

advanced tumors, PSA levels can be increased both by soft-

tissue and bony metastases; therefore, metastatic disease to bone

is not monitored directly.

The aim of the present study was to describe an improved

bone scan interpretation technique for quantifying the amount of

total skeleton that was involved by osseous metastatic disease

(the BSI). We sought to determine the precision and accuracy of

this scan interpretation in patients with prostate carcinoma and

to compare it with the PSA response during treatment and with

the normal adult bone marrow distribution. To explore in this

way the biological relevance of the BSI in regard to the patho-

physiology of bone metastases in prostate cancer, we used a

visual method of analysis, which proved suitable for our initial

correlation of BSI with tumor progression and response. An

advantage of the visual method was that digitized scans were not

required, and we could study a larger series of patient studies,

going back several years in some cases.

MATERIALS AND METHODS

Patient Population. Two hundred sixty-three bone scans

were performed on 90 patients being treated for AIPC. In all

patients, the diagnosis of prostate cancer was confirmed by Iran-

srectal biopsy. Blood samples for PSA measurements were ob-

tamed from each patient before whole-body bone scintigraphy.

Normal serum PSA concentrations ranged from 0 to 4 ng/ml.

Bone Scintigraphy. Bone scans were performed 3 h after

the iv. injection of 740 MBq (20 mCi) of Tc-99m methylene

diphosphonate. Whole-body images (and static images when mdi-

cated) were obtained using a dual-head gamma camera (ADAC;

Genesys) equipped with a low-energy, high-resolution collimator at

a scan speed of 20 cm/mm. Bone scans were read by independent

reviewers who were blinded to the patient’s clinical condition.

Bone Scan Quantitative Analysis. To provide a quanti-

tative measure of the extent of metastatic bone disease, the bone

scans were analyzed according to the following criteria. One hun-

dred fifty-eight individual bones in the body were listed by name.

The weight of each bone, expressed as a fraction of the weight of

the entire skeleton, was determined based on ICRP publication No.

23 (10). The fractional involvement of each bone by tumor was

estimated visually from the bone scan. The BSI was then calculated

by summing the product of the weight and the fractional involve-

ment of each bone expressed as percentages of the entire skeleton.

Inter- and Intraobserver Variability of Bone Scan In-

terpretation. The interobserver variation was tested on 69

bone scans from the first 1 8 consecutive patients (mean age,

69 ± 4) with stage D prostate cancer who were entered on a

treatment protocol at MSKCC between January 1990 and Feb-

ruary 1994. These bone scans were read by three independent

reviewers who were blinded to the patients’ condition, as well as

the results of the other reviewers’ readings. This was done after

the three observers participated in a training session that last

about 3 h and involved 10 images in which they graded the

images together to reach consensus.

To assess intraobserver variability, one scan for each of the

18 patients was re-read by two readers at 2-year intervals (the

first time in July 1995, and the second time in July 1997). A



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Fig. 1 Typical whole-bodybone scan in a patient with pro-gressive prostate cancer, oh-tamed at four different intervalsafter the first bone scan abnor-mality was observed in the rightischium, showing progression.

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Clinical Cancer Research 1767

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simple correlation’s analysis was used to assess the intraob-

server variability.

Comparison of Changes in Serial BSI to Changes in

Serial PSA. A comparison was made between changes in the

BSI and PSA in 27 patients with AIPC who participated in a

treatment protocol with hydrocortisone followed by suramin at

PSA relapse. Twenty-four of these patients had sufficient serial

bone scans for comparison (an average of 4.3 bone scans!

patient). These bone scans were read by two readers and when

there was a discrepancy in BSI, a consensus reading was re-

corded. There was an average of 28 PSA values per patient. A

Pearson’s moment correlation analysis was used to correlate the

changes in PSA and BSI over time.

Distribution of Metastases in Limited Bone Involve-

ment by AIPC (<3% of the Skeleton). The baseline bone

scans of 27 patients with AJPC and limited bone involvement

were analyzed in regard to regional distribution within the

skeleton, and in particular with respect to the distribution of the

normal adult bone marrow (1 1). A total of 136 lesions were

found and plotted onto a composite representation of the distri-

bution of the normal adult skeleton.

Progression of AIPC. Twenty-one patients were found

among patients who were being treated for AIPC who had a

baseline scan for which the BSI was 3% or less and who

progressed to above 3% in a subsequent scan. In all, a series of

62 bone scans were obtained, and the BSI was plorted as a

function of time of observation. The data that was obtained was

fit to a Gompertzian equation (12), which describes an expo-

nentially declining exponential growth rate (13) and appears to

describe solid tumor growth patterns relatively well.

RESULTSInter- and Intraobserver Variability of BSI. A typical

whole-body bone scan from a patient with AIPC is shown in

Fig. 1 with the corresponding BSI. The initial involvement in

the bone progressed quite slowly from January 24, 1990 to May

20, 1990. When the patient developed a rapidly increasing PSA,

a follow-up bone scan was ordered in April 1991, which showed

a marked change from prior scans. Also, in the 2-month period

to June 27, 1991, there was considerable progression of the

lesions in the right upper humerus and right hip. Because there

had been no change in management up to this point, flare

phenomenon is unlikely as a cause of the bone scan progression.

The interobserver variability of the test is shown in Fig. 2.

Fig. 2a shows the three readers’ estimates of the percentage of

bone involvement with the scans ordered by the average of the

three readers’ estimates for easier visualization. The ordinate is

the BSI, and the abscissa is the scan number, ranked in order of

the average of the three readers’ scores. As can be seen in Fig.

2, a and b, the average BSI of the three readers varied from 0 to

5 1 % in this series of bone scans. A typical “super-scan” of



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prostate cancer would be in the range of 30-50%. The absolute

variability among readers increases somewhat at the very high-

est values. However, Fig. 2b shows that the cube root transfor-

mation of the three readers’ estimates of the percentage of bone

involvement stabilizes the variance over the entire range of

analysis, and this simplifies the interpretation of BSI variation

between observers. The curve for reader 1 abruptly goes to zero

at scan 27 because no reading was available here. Fig. 2c shows

the individual reader’s behavior as a function of the other two,

i. e., every reader’ 5 deviation from the cube root of the average

BSI of the other two readers, plotted as a function of the average

BSI of the other two readers. For the most part, the deviations

are scattered along the y 0 line (x-axis), indicating that any

systematic difference between the readers tends to be small.

There are some trends that are apparent; for example, at the

larger BSI values, reader 3 tended to have a higher value than

the average of the other two readers.

After a period of 2 years, the intraobserver variability was

minimal, showing a correlation coefficient of 0.97 for reader 1

(Fig. 3a) and 0.99 for reader 2 (Fig. 3b), P < 0.001. The same

reader agreed with his previous reading of the BSI, even after a

considerable time gap. Thus, in summary, the reliability of BSI

has been characterized; moreover, there is excellent reproduc-

ibility of intraobserver observations.

Comparison of Changes in Serial BSI to Changes in

Serial PSA. With regard to the comparison between BSI and

PSA, 27 patients with AIPC had scans available, of which 24

patients had sufficient serial bone scans for comparison (an

average of 4.3 bone scans/patient). These results have been

published previously in abstract form (14). The median time

between BSI determinations was 75 (47-1 10) days, with a 25%

median change (18-35%) between studies. The median time

between PSA determinations was I I (7-26) days, with a 6%

median change between values per patient. On average, there



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were 4.3 BSI determinations per patient and 28 PSA values per

patient. There was a generally parallel rise in PSA and BSI, with

a strong concordance between BSI and PSA change with a

Pearson’s moment correlation of 0.71 (P < 0.0!).

Fig. 4 shows two examples of how the BSI might be used

to monitor response. The change in PSA and the BSI show a

similar trend in these examples. In Fig. 4a, the gradual increase

in PSA and the gradual increase in BSI paralleled one another

for about 6 months, at which time there was a rapid increase in

BSI involvement, followed later by an increase in PSA. In Fig.

4b, the patient underwent rhenium-!86 therapy and showed a

dramatic response to treatment, as demonstrated by the decrease

in both PSA and BSI over time, with a much larger and earlier

drop in PSA. At day 450, there was a marked upswing in both

PSA and also the BSI. In this instance, the BSI and PSA

appeared to correlate better in progression than in response.

Distribution of Metastases in Limited Bone Involve-

ment by AIPC with <3% of the Skeleton Initially Involved

by Tumor. The distribution of metastatic lesions within the

skeleton was studied in a group of 27 patients with AIPC who

were being treated under two treatment protocols at MSKCC.

These 27 patients had BSI <3% and were considered to have

limited disease, in contrast to the balance of patients in this

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Fig. 4 Comparison of BSI and PSA. a, patient with prostate carcinoma

showing a parallel increase of the bone scan index and PSA levelsduring a period of 2 years, with rise in BSI preceeding PSA. b, patient

with prostate carcinoma who underwent rhenium- I 86 therapy and

showed a dramatic response to treatment as demonstrated by the de-crease in both PSA and BSI over time. The arrows indicate treatmentwith rhenium-186.

group with more extensive tumor involvement. The distribution

of metastatic lesions in the skeleton was determined. There were

a total of 136 lesions in these patients, and the pattern of

distribution is shown as a black dot placed at the site of tumor

involvement on a model of the skeleton shown in the anterior

and posterior projection (Fig. Sa). It can be seen that the distri-

bution is not random in the skeleton; instead, the tumor clusters

in the axial skeleton, ribs and proximal limbs. The metastatic

pattern shows a remarkable parallel with the distribution of the

normal adult bone marrow distribution (Fig. Sb). We have

interpreted these results as being consistent with the view that

the distribution of early metastatic tumor from AIPC is coex-

tensive with the normal red marrow in the adult and suggests

that the marrow may be a particularly favorable environment for

growth of AIPC tumor.

Rate of Progression of AIPC. In a group of three pro-

tocols treated for AIPC, we evaluated patients who were pro-

gressing during serial scan studies. Because the natural history

of prostate cancer is variable, we defined progression as going

from low-volume disease (<3% of skeletal involvement) to

progress above 3% in a subsequent bone scan, regardless of

bone scan interval. Of the 21 follow-up bone scans, the median

first follow-up was 108 days after baseline, with a range of



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Fig. 6 Progression of bone involvement by prostate cancer. Exampleof progression by BSI from early involvement (<3%) to late involve-ment of prostate cancer using a Gompertzian equation model.


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Fig. 5 a, pattern of metastatic bone disease in 27 patients with <3%

BSI. b, normal adult pattern of bone marrow distribution.

30-1770 days. The BSI of all available scans in this group of

patients was plotted as a function of the time after baseline. In

all, 2 1 patients and 62 scans were analyzed, and the data are

plotted in Fig. 6. The data were fitted to a Gompertzian equation

of the form BSJ(t) BSl0exp[a/b(l - exp(-bt))], where BSJ0

represents the BSI at time zero at the baseline, a represents the

growth rate at time zero, b represents the rate at which the

growth rate slows down, and t is the time in days after the

baseline scan. The parameters in the equation that best fit the

data were determined by minimizing the sum of the squares of

the residuals using the Levenberg-Marquardt method (15).

The fit parameters were as follows: BSI0 = 3.3%; a =

0.00485; and b 0.00254. The progression that was observed

was most rapid initially, and then the growth rate gradually

diminished as more time elapsed from the index scan. This

corresponds to a starting doubling time of 43 days, which

rapidly diminished with time. We have interpreted these results

to be consistent with a Gompertzian growth pattern in which

there is more rapid expansion of tumor in the early phase of

growth, reflecting a more highly favorable environment for

growth of the AIPC tumor. As time goes by, however, there is

a gradual loss of favorable conditions, and the growth slows.

DISCUSSION

We developed the BSI method with two goals in mind: (a)

the approach should lend itself to automation; and (b) the

method should measure information that is biologically relevant

to the pathophysiology of bone involvement by prostate cancer.

The bone scan is widely accepted as a valuable tool for

monitoring extent of tumor in bone metastases (16, 17), and a

number of authors have developed semiquantitative methodol-

ogy for assessing bone involvement and response and the extent

of tumor involvement (18). In particular, Soloway et a!. (6)

graded the extent of disease into five categories based on the

number of bony metastases read on the bone scintigraphy. Such

techniques do have value in permitting a stratification of pa-

tients in the extent of bone involvement, and at the extremes,

i.e., few lesions versus massive number of lesions, there is a

correlation with prognosis. Semiquantitative bone scanning

methods based on counting the number of lesions are not easily

automated, however. Also, when lesions increase in number and

become confluent, the number of lesions can actually drop, even

when the patient is progressing. Because of these limitations,

simpler methods based on scoring or grading schemes have been




proposed. Knudson et a!. (19) divided the skeleton into five

skeletal areas: vertebrae, ribs, pelvis, long bones, and skull.

Patients were stratified according to the number of skeletal areas

involved. Other methods for bone scan interpretation have used

simple scoring system ranging from 0 to 2, with 0 representing

normal uptake, 1 representing single or several uptakes, and 2

diffuse uptake (20). More recently, Jinnouchi et a!. (21) have

proposed a different method for quantitation of changes in serial

bone scintigrams in patients with carcinoma of the prostate

using fixed-size regions of interest placed relative to anatomical

landmarks. These methods could be easily automated, at least in

principle, but much useful information is lost in these simplified

approaches, such as the anatomical information about which

bones are involved or progressing, so that correlation can be

readily made with other diagnostic information. The net result is

that none of these semiquantitative methods have been adopted

clinically on a large scale.

The BSI method, which is based on fractional involvement

of the skeleton on a bone-by-bone basis, will be more amenable

to computerized automation, based on segmentation and thresh-

olding approaches, in comparison with other quantitative tech-

niques developed previously. In fact, a method of threshold

analysis, which we believe will permit computerized image

interpretation of BSI, has been developed at MSKCC (22). We

are in the process of transferring this approach from a silicon

graphics platform to a more readily accessible PC environment.

This preliminary study shows that the BSI is a reliable

method for quantitative interpretation and assessment of bone

scan extent or progression of metastases in patients with prostate

cancer. The variability of the three readers was individually

assessed in relationship to the average of the other two readers

and appears to increase as the BSI increases. Hence a cube root

transformation was performed empirically to stabilize the van-

ance, so that a direct comparison between readers could be

made. In general, it can be said that the variability between

readers is acceptably low. Similarly, the reproducibility based

on a linear correlation between two readings of readers 1 and 2,

as shown in Fig. 3, is also small, with a mean difference of 1.3%

BSI over the range of 2-54%. Thus, intraobserver variability of

the visual BSI was excellent and, as expected, was significantly

less than the interobserver variability.

In considering how we evaluated the validity of the BSI,

certain facts about prostate cancer should be kept in mind. The

natural history of clinically evident prostate cancer is gradual

progression, from organ-confined tumor to spread both by lym-

phatics to locoregional lymph nodes and hematogeneously to

distant sites. Once tumor has spread beyond the prostate gland,

it is essentially incurable. Prior to treatment of metastatic pros-

tate cancer, the tumor of individual patients is composed of cells

of three distinct phenotypes: androgen-dependent, androgen-

sensitive, and androgen-independent (23). Initially, most pa-

tients with advanced prostate cancer do respond to androgen

withdrawal, because the bulk of the tumor at this stage of the

disease is, like normal prostatic cells, androgen dependent, so

that the cells stop proliferating and in fact die when androgen is

withdrawn. During this phase of treatment, the androgen-sensi-

tive cells stop growing, and the androgen-independent cells are

unaffected by the treatment but continue to slowly proliferate.

These cells are sensitive to other growth factors, including

various stimulatory substances found in the bone and bone

marrow. This may explain in part why prostate cancer shows a

propensity to spread to bone as the most important and in some

cases the sole site of metastatic involvement. The cells initially

are seeded to the marrow space, where there is a rich microen-

vironment that favors growth. The involvement of the bones

themselves is a secondary phenomenon, as the tumor cells in the

bone marrow expand.

As androgen-independent clones proliferate, often within

the bones, the tumor becomes unresponsive to hormonal sup-

pression and androgen-independent sites of tumor evolve. PSA

levels begin to rise. In fact, progressive increase in PSA usually

begins a few months before symptomatic evidence of relapse

occurs. Changes in PSA levels have also been shown to have

major prognostic impact, and patients who do not normalize

their PSA values after treatment have a poor prognosis (24).

It is also clear from studies by Sabbatini et a!. (25) that BSI

itself is a powerful independent predictor of the prognosis for

such patients and will help select patients who may be candi-

dates for very aggressive therapies because of otherwise poor

prognosis. For example, in a separate group of 1 9 1 patients with

AIPC who were treated with liarozole versus prednisone, and

whose data are not included in this report, the BSI values of

< 1.4%, 1.4-5.1%, and >5.1% divided the study group into

patients with corresponding median survivals of 18.3 months,

15.5 months, and 8.1 months, respectively (P < 0.0079).

In assessing the validity of the BSI method as an indicator

of bone involvement by prostate cancer, we focused on a com-

parison of BSI to PSA, because PSA is presently considered to

be the best cancer marker for progression. Although the BSI

represents a very different feature of bony metastases, changes

in BSI show good correlation between the changes in PSA

during disease progression. The type of correlation that was

used, the Pearson’s moment correlation, is used for rank order

correlation and is not sensitive to absolute levels of the variable

compared. The correlation was highly significant on a statistical

basis. As seen in Fig. 4, the correlation in these individual patients

appears to be best in progressing disease, and during response the

BSI is likely to be significantly slower to change. However, we did

not have a large enough group of PSA responders to systematically

study this phenomenon in the present series.

Furthermore, interesting biological correlates can be drawn

based on the BSI in terms of a match between the distribution of

metastatic disease in early AIPC and the normal adult bone

marrow and a Gompertzian pattern of skeletal involvement by

AIPC during progression.

In the normal adult, red marrow is found in the central

skeleton (skull, thorax, pelvis, and spine) and the upper portion

of the femurs, humeri (Fig. 5). In the present study, patients with

low-volume tumors (i.e., <3% BSI) displayed a distribution of

metastases in a manner corresponding to the distribution of the

normal adult bone marrow. This is supportive of the notion that

the initial seeding and attachment of the tumor cells occur

within the red marrow, followed by expansion during growth to

adjacent bone (2).

Finally, the BSI has been graphically explored as a function

of time after diagnosis. The progression of bone scan changes in

AIPC, from early involvement (<3%) to late involvement (Fig.

6), shows a relatively rapid increase initially, followed by a




slowing of expansion as time elapses from baseline bone scans.

The data as plotted match well to a Gompertzian pattern of

growth, which describes an exponentially decreasing growth

rate and is the usual growth pattern of solid tumor (13).

Based on Fig. 6, it is possible to make recommendations

regarding the frequency of bone scanning in following patients

with AIPC. During the early proliferative stage of androgen-

independent tumor when the PSA begins to rise, bone scan

changes occur very rapidly. At this stage, bone scans should

probably be obtained every 4-6 weeks to help in deciding when

to introduce chemotherapy. However, once the bone scan in-

volvement has progressed to 10%, the rate of growth is consid-

erably slower, and bone scans could be obtained every 3

months. When the bone scan is more than 10%, changes will be

considerably slower, and six monthly scans should be sufficient

to monitor the process, unless the patient is under active treat-

ment with some evidence of response.

We conclude that the BSI as developed and implemented at

MSKCC allows a reproducible estimate of the percentage of

skeleton involved by tumor in patients with metastatic prostate

carcinoma. This approach appears accurate for demonstrating

progression of prostatic cancer metastases to bone. There is a

highly significant correlation between changes in PSA, a known

parameter of progression, and BSI. Also, BSI data indicate that

early tumor involvement of bones is coextensive with the dis-

tnibution of red marrow. Initial involvement of bone by AIPC is

quite rapid, with a doubling time of 43 days or less, followed by

a gradual slowing of the rate of involvement. Taken together,

the findings of the present study are consistent with the hypoth-

esis that the BSI represents a valid and reliable new parameter

for quantitative assessment of bone involvement by AIPC. Ac-

cordingly, we are presently evaluating BSI as a tool for bone scan

interpretation in situations where monitoring of treatment response

is an essential feature of patient management. In addition, it is

possible that the BSI may prove to be useful for stratifying patients

according to their likelihood of response to particular therapies,

based on total extent of tumor in bone, and thus help select the most

appropriate therapy for the individual patient.

ACKNOWLEDGMENTS

We thank Dr. George Sgouros, who gave useful advice about the

use of 1CRP reference guides for bone weights.

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1998;4:1765-1772. Clin Cancer Res M Imbriaco, S M Larson, H W Yeung, et al. prostate cancer: the Bone Scan Index.A new parameter for measuring metastatic bone involvement by

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