Acta Radiologica

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Evaluation of New Sclerotic Bone Metastases in

Breast Cancer Patients During Treatment

I. Çiray, G. Åström, I. Andréasson, T. Edekling, J. Hansen, J. Bergh & H.

Ahlström

To cite this article: I. Çiray, G. Åström, I. Andréasson, T. Edekling, J. Hansen, J. Bergh & H.
Ahlström (2000) Evaluation of New Sclerotic Bone Metastases in Breast Cancer Patients During
Treatment, Acta Radiologica, 41:2, 178-182

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Acta Radiologica 41 (2000) 178–182 Copyright C Acta Radiologica 2000
Printed in Denmark ¡ All rights reserved
AC TA R A D I O L O G I C A
ISSN 0284-1851

EVALUATION OF NEW SCLEROTIC BONE METASTASES

IN BREAST CANCER PATIENTS DURING TREATMENT

I. Ç1, G. Å̈1, I. A́2, T. E3, J. H4, J. B2 and H. A̈1

Departments of 1Diagnostic Radiology and 2Oncology, University Hospital, Uppsala, 3Department of Oncology, Central
Hospital, Växjö and 4Department of Oncology, Central Hospital, Västerås, Sweden.

Abstract
Purpose: According to the World Health Organization (WHO) criteria for Key words: Bone neoplasm,
response of bone metastases to therapy, new lesions indicate progressive disease. metastases; sclerosis; radiography,
We intended to prove that a new sclerotic lesion on conventional radiography radionuclide studies.
may also be a sign of a positive therapeutic response in a previously undetect-
able lytic metastasis. Correspondence: Ipek Çiray,
Material and Methods: In a previous placebo-controlled clinical trial of clod- Department of Diagnostic
ronate (Ostac) therapy, 139 breast cancer patients with bone metastases under- Radiology, University Hospital,
went both conventional radiography and bone scan every 6 months for 2 years SE-751 85 Uppsala, Sweden.
with 99mTc before and during clodronate treatment. WHO criteria were applied FAX π46 18 66 48 06.
for therapy response evaluation.
Results: In 24 patients, 52 new sclerotic lesions observed during therapy were Accepted for publication 25 October
selected for re-evaluation of conventional radiographs and bone scans. In 8 of 1999.
the 24 patients, 17 of 52 new sclerotic lesions (33%) had showed positive uptake
on previous bone scans. These lesions were possibly misinterpreted as new when
applying WHO criteria.
Conclusion: For better assessment of new sclerotic lesions during treatment,
more sensitive techniques, e.g. bone scan, are needed as a complement to con-
ventional radiography.

The follow-up of diagnosed bone metastases dur-
ing systemic therapy is a major clinical problem,
which is frequently encountered in breast cancer
patients, in whom the skeleton is often a site for
metastatic spread. The objective assessment of tu-
mour response in the skeleton to different oncolog-
ical therapeutical modalities is a considerable chal-
lenge. This is mainly due to the fact that radiologi-
cally detectable lesions often persist even after
successful systemic treatment (14). For these rea-
sons, patients with metastases at skeletal sites
alone are frequently excluded from clinical trials.
In 1977, the International Union Against Can-
cer (IUCC) suggested a method for objective
evaluation of response of breast cancer bone meta-
stases to therapy, basing their criteria on radio-
graphic changes (12). These criteria were extended
and reformulated by the World Health Organiza-
tion (WHO) for all kinds of tumour metastases to
bone (results from two meetings, Turin in 1977 and
Brussels in 1979 (19)). These criteria have been
widely applied both in routine practice and in clin-
ical trials. According to the WHO criteria (Table
1), new lesions indicate progressive disease (PD)
regardless of whether they are sclerotic or not.
However, this may not be correct, as sclerosis may
be a sign of a positive therapeutic effect (10, 16).
However, it might be difficult to differentiate new
sclerotic lesions caused by progression of the dis-
ease from those representing healing of lytic lesions
that were not detected on the pretreatment radio-
graphs (9, 17), since it is known that more than
50% of the trabecular bone has to be destroyed
before the lytic lesion can be detected on conven-
tional radiography (7). This might lead to misin-
terpretation of the response of bone metastases to

178
 NEW SCLEROTIC BONE METASTASES FROM BREAST CANCER DURING TREATMENT

Table 1 monal treatment, and chemo- and radiotherapy

according to standard indications. These therapy
WHO criteria for objective response of bone metastases to
therapy modalities were changed if clinical and/or radio-
logical investigations revealed PD.
1. Complete response Complete disappearance of all lesions on
radiography or scintigraphy for at least 4 weeks
In the clinical trial, besides the clinical and lab-
2. Partial response Decrease in size of lytic lesions, recalcification oratory tests, all patients were examined prospec-
of lytic lesions, or decreased density of blastic tively with both whole body bone scan and con-
lesions for at least 4 weeks ventional radiography before and at 6-month in-
3. No change Because of the slow response of bone lesions
the designation ‘‘no change’’ should not be
tervals during the medication with clodronate or
applied until at least 8 weeks have passed from placebo. Bone scans were recorded using a conven-
start of therapy tional gamma camera after the injection of 99mTc-
4. Progressive disease Increase in size of existent lesions or labelled pyrophosphate or diphosphonate. In each
appearance of new lesions patient, anterior and posterior views as well as ob-
lique and lateral views of the whole skeleton were
included in the bone scan. Plain radiographic ex-
aminations included one or more of the following
therapy. Although this phenomenon has been well areas: Skull, cervical spine, thoracic spine, lumbar
recognised (3, 6), to our knowledge it has not been spine, pelvis, both femurs and/or arms, according
shown in a clinical study. to the clinical symptoms or the areas of patholog-
The possible effect of clodronate on bone meta- ical uptake seen on the radionuclide bone scans.
stases from breast cancer was evaluated using the Plain radiographs was performed in lateral and
WHO criteria (A́ et al., unpublished frontal views of the skull, spine and limbs, and in
data) in a prospective placebo-controlled phase III a frontal view of the pelvis.
trial carried out at three hospitals (Uppsala Uni- Response to treatment was assessed by evalu-
versity Hospital, Västerås and Jönköping County ation of the conventional radiographs using the
Hospitals) between 1990 and 1993. In this trial,
new sclerotic changes were found in some of the
patients at the regular follow-up visits every 6
Table 2
months. In the present study, we conducted a
radiological re-assessment of those breast cancer Topographic distribution of all new lesions found during therapy
in 24 patients with new sclerotic lesions
patients who showed new sclerotic lesions during
the clodronate trial period in order to investigate New sclerotic New lytic New mixed Total
the possibility of misinterpretation by the appli- Skull 1 3 1 5
cation of the WHO criteria. Cervical spine 2 3 0 5
Thoracic spine 9 5 2 16
Lumbar spine 8 3 3 14
Material and Methods Pelvis 13 2 2 17
Ribs 4 2 2 8
Clodronate (Ostac) clinical trial: After receiving Femur, bilateral 14 4 1 19
oral and written information, a total of 139 breast Arm, bilateral 1 2 0 3
Total 52 24 11 87
cancer patients with previously histologically con-
firmed recurrent disease or primary skeletal meta-
stases with or without other organ metastases
agreed to be included in a multicentre placebo-
Table 3
controlled phase III clinical trial with clodronate
(Ostac, Boehringer Mannheim) carried out be- Results of the comparison of conventional radiography showing
tween September 1990 and May 1993. This clinical new sclerotic lesions with the previous bone scan
study was designed to investigate the possible ef- Previous bone Previous bone Total
fect of clodronate on skeletal metastases. Criteria scan, π scan, ª

for exclusion from the study were: Other malig- Skull 0 1 1

nancy, pregnancy, S-Ca ⬎2.7 mmol/l, life expect- Cervical spine 2 0 2
ancy ⬍3 months, use of another investigational Thoracic spine
Lumbar spine
3
2
6
6
9
8
drug less than 30 days, inflammatory bowel disease Pelvis 5 8 13
and likelihood of not maintaining good compli- Ribs 0 4 4
ance. The patients received 2 years of treatment Femur, bilateral 5 9 14
with capsules of clodronate 2,400 mg/day or pla- Arm, bilateral 0 1 1
Total 17 35 52
cebo in identical capsules. They also received hor-

179
 I. ÇIRAY ET AL.
Fig. 1. A 65-year-old breast cancer patient with known skeletal
metastases. a, b) A round sclerotic lesion (») appeared in the
left femur during the follow-up which at the radiological evalu-
ation of the clinical trial was interpreted as indicating progress-
ive disease according to the WHO criteria. c) Previous bone
scan revealed earlier existence of the lesion (➤).
WHO criteria (Table 1). All conventional radio-
graphs were evaluated by a single observer (H.A.),
and if present, new lesions and their topographic
locations were noted. Of the 139 patients who
Fig. 2. Radiographic cervical spine examination of a 52-year-old patient. a) Before the clodronate treatment and b) at the first year
of follow-up, at which time there is a new sclerotic lesion in the C6 vertebral body (⇒). c) On the bone scan before the clodronate
treatment, positive uptake is seen in the same vertebra (➤).
180
entered the clinical trial of clodronate versus pla-
cebo, 45 patients were interpreted during the trial
as having PD on the basis of the appearance of
new skeletal lesions according to the WHO cri-
teria.
Evaluation: All conventional radiographs and
radionuclide bone scans of these 45 patients (39–
79 years old, median 60 years) were re-evaluated
by three observers in consensus (I.Ç., G.Å., H.A.).
‘‘New’’ lesions were noted and the nature of the
new lesions was identified as sclerotic, lytic or
mixed-lytic and sclerotic.
Conventional radiographs showing new sclerotic
lesions were compared with bone scans obtained 6
months prior to determine whether or not there
had been positive uptake in the areas where appar-
ently new sclerotic lesions appeared.
Results
Of the 45 patients, 24 had new sclerotic lesions. In
these 24 patients, besides a total of 52 new sclerotic
lesions, 11 new mixed-lytic and sclerotic and 24
new lytic lesions were recorded. The topographic
distribution of new lesions in these patients is given
in Table 2.
In 16 of the 24 patients (67%) with new sclerotic
lesions, there was no pathologic uptake on pre-
 NEW SCLEROTIC BONE METASTASES FROM BREAST CANCER DURING TREATMENT
vious bone scans in the areas where new sclerotic
lesions appeared on conventional radiographs
after 6 months. The lesions in these 16 patients
were thus judged to be truly new and were classi-
fied as a sign of PD when applying the WHO cri-
teria. In the remaining 8 patients (33%), positive
uptake was observed in the corresponding areas on
previous bone scans. In 2 of 8 patients with new
sclerotic lesions, new lytic and/or mixed lesions
were also observed at the same time but in other
sites. The remaining 6 patients were considered as
possibly misinterpreted as having PD.
The results of the comparison between conven-
tional radiography and bone scan for new sclerotic
lesions in different sites are given in Table 3. In 8
patients, 17 new sclerotic lesions were detected
with previous positive uptake on bone scans (Figs.
1, 2). These lesions were considered as possibly
misinterpreted as new and a sign of PD when ap-
plying the WHO criteria.
Discussion
WHO criteria have been established to develop a
‘‘common language’’ to describe the results of can-
cer treatment and to agree upon internationally
acceptable general principles for reporting and as-
sessing data (15). But at present, considering the
shortcomings of conventional radiography and the
availability of other modalities, the existing criteria
for objective evaluation of the response of bone
metastases to treatment need to be modified, ex-
tended and improved. This is necessary not only
for determining the best treatment, but also to
allow objective and accurate evaluation of the ef-
fects of new therapies on bone metastases in clin-
ical trials. This is a very important issue, since pa-
tients with bone metastases are often excluded
from clinical trials. Treatment of this group is im-
portant, and every effort should be made to optim-
ise the objective assessment of their response. The
present study was conducted in this context.
By verifying pathological uptake in bone scans
in the same sites where new sclerotic lesions ap-
peared on radiographs we showed that 17 of the
52 (33%) new sclerotic lesions were possibly misin-
terpreted as a sign of PD when using the WHO
criteria. The low sensitivity of conventional radi-
ography in revealing early metastatic lesions is sug-
gested as the main reason for this possible misin-
terpretation. Many authors have considered serial
conventional radiographs to be unreliable as the
sole means of assessing the response to therapy or
PD (4, 17). Our results did confirm that conven-
tional radiography by itself was not ideal for evalu-
ating the response of bone metastases to therapy
in the case of new sclerotic lesions.
The disadvantages of bone scans, such as low
specificity and low spatial resolution, are also well
recognised. Although bone scan lacks specificity,
it is highly sensitive in detecting bone metastases.
According to the results of K et al. (13) in
380 consecutive breast cancer patients, sensitivity
and specificity of the bone scan were found to be
96% and 66%, respectively.
Some authors suggest that serial bone scans can
be used to monitor the response of bone meta-
stases to therapy (4, 17). It seems that a combi-
nation of the specificity of radiography and the
sensitivity of bone scan may provide additional in-
formation. In this study, by combining the re-
evaluation of radiographs and bone scans, we were
in some cases able to distinguish the new sclerotic
lesions that might be a sign of a positive thera-
peutic effect from truly new sclerotic lesions con-
sistent with PD. On the other hand, decreased
radionuclide uptake can be interpreted as either
therapy response or increased lysis; and increased
radionuclide uptake can be interpreted as a sign of
healing response (flare phenomenon) or as disease
progress (5). Furthermore, some comparative
studies have shown that MR maging is more sensi-
tive than bone scanning (1, 2, 11). Considering
this, the incidence of misinterpretation of new
sclerotic lesions as a sign of PD is possibly higher
than suggested in our study.
We believe that the initial nature of the lesion
also has an impact on the assessment of new
sclerotic lesions with previous positive bone scan.
In patients who previously had purely lytic bone
metastases or no lesions, a new sclerotic lesion
with positive uptake on the previous bone scan
most probably is a sign of a positive response to
therapy. However, in patients in whom new sclero-
tic lesions arise, and in whom there was a previous
mixture of lytic and sclerotic metastatic lesions or
pure sclerotic metastases in other sites, there may
be an interpretation problem. Although the pre-
vious positive bone scans prove that these new
sclerotic lesions in fact are not new lesions and so,
may be signs of positive therapeutic response in
previously undetectable lytic lesions; they may also
represent progression in size of previously un-
detectable sclerotic lesions. Neither radiography
nor bone scan, nor a combination of the two, can
always differentiate between these two possibilities.
In routine practice at various centres, assess-
ment of the response to therapy relies on conven-
tional radiographs alone, bone scans alone or
both. Advanced techniques such as CT and MR
should probably be considered as supplement in
181
 I. ÇIRAY ET AL.
this respect, but this has not yet been established.
Although there are several reports showing high
sensitivity and specificity of these methods in de-
tecting the skeletal metastases, there are only few
reports describing the possibility of objectively
evaluating the response of bone metastases to ther-
apy using these techniques (8, 18). The costs and
availability of these techniques compared to con-
ventional radiography and bone scan should also
be considered. More comparative studies including
all of these methods are required for determining
the best assessment of therapy response of bone
metastases.
ACKNOWLEDGEMENTS
This study was supported by grants from the Swedish Society
of Medicine and from the Swedish Cancer Society. The placebo-
controlled study with clodronate was supported by grants from
Boehringer Mannheim Scandinavia AB.
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