Review

Radioisotopes for the palliation of metastatic bone cancer:

a systematic review
Ilora G Finlay, Malcolm D Mason, Mike Shelley

Lancet Oncol 2005; 6: 392400

See Reection and Reaction
page 353

Strontium-89 and samarium-153 are radioisotopes that are approved in the USA and Europe for the palliation of
pain from metastatic bone cancer, whereas rhenium-186 and rhenium-188 are investigational. Radioisotopes are
effective in providing pain relief with response rates of between 40% and 95%. Pain relief starts 14 weeks after the
initiation of treatment, continues for up to 18 months, and is associated with a reduction in analgesic use in many
patients. Thrombocytopenia and neutropenia are the most common toxic effects, but they are generally mild and
reversible. Repeat doses are effective in providing pain relief in many patients. The effectiveness of radioisotopes can
be greater when they are combined with chemotherapeutic agents such as cisplatin. Some studies with 89Sr and 153Sm
indicate a reduction of hot spots on bone scans in up to 70% of patients, and suggest a possible tumoricidal action.
Further studies are needed to address the questions of which isotope to use, what dose and schedule to use, and
which patients will respond.

See Media Watch page 367 for a

book review on bone-cancer
metastasis
Department of Palliative
Medicine (Prof I G Finlay FRCP),
Urological Cancers Review
Group (Prof M D Mason FRCR,
M Shelley PhD), Velindre NHS
Trust, Velindre Hospital,
Whitchurch, Cardiff, Wales, UK
Correspondence to:
Dr Mike Shelley, Cochrane
Prostatic Diseases and Urological
Cancers Group, Cochrane Unit,
Research Department, Velindre
NHS Trust, Whitchurch, Cardiff,
Wales, CF14 2TL, UK.
mike.shelley@velindretr.wales.nhs.uk

Introduction

Du Cane Medical Imaging/SPL

Metastatic bone cancer is a common and severe

complication in advanced disease. It develops in up to
70% of patients with prostate cancer and breast cancer,
and in up to 30% of those with cancers of the lung,
bladder, and thyroid (gure 1). The major complications

Figure: Coloured spinal radiograph of a man with sclerotic vertibrae (purple)

caused by metastatic prostate cancer

392

associated with bone involvement are severe pain,

spinal-cord compression, and pathological fractureall
of which restrict mobility and sleep, greatly reducing the
patients quality of life. The scale of the clinical problem
is substantial, since cancers of the prostate, breast, and
lung account for about 45% of cancers in all sites.1
The development of bone metastases is complex,
involving many processes at the primary site, including
tumour-cell proliferation, cell-matrix detachment, cell
migration, angiogenesis, and intravasation. The tumour
cells are carried via the vasculature or lymphatic system
to the bone marrow, where the complex capillary
structure and the slow blood ow aid metastatic
development.2 Bone lesions are commonly radiographically classied as osteolytic, when bone
destruction arises by the action of osteoclasts (as seen in
patients with breast cancer), or osteoblastic, which
predominates in prostate cancer and is characterised by
sclerosis. However, a mixed pattern is common in many
lesions, and marker studies suggest that both resorption
and formation occur simultaneously.3 The exact
mechanism of cancer-induced bone pain is not known.
It manifests in three distinct forms, tonic or background
pain that is a deep non-specic ache rising in intensity as
the disease progresses, incident pain on movement
(allodynia), which renders patients virtually immobile,
and spontaneous pain that can be severe.4
The management of patients with metastatic bone
pain must be a multidisciplinary approach and includes
the use of analgesia, radiotherapy, surgery, chemotherapy, hormone treatment, radioisotopes, and
bisphosphonates. Analgesia, with non-steroidal antiinammatory drugs, is the rst option in most patients,
progressing to stronger opioids as the intensity of pain
rises. These drugs produce unwanted side-effects such
as nausea, sedation, and constipation. Radiotherapy or
surgery can be used for localised metastatic disease, and
hemibody radiotherapy might be suitable for patients
with disease extending to one region of the body. In
patients with widespread painful bone involvement,
http://oncology.thelancet.com Vol 6 June 2005

Review

bone-seeking radiopharmaceuticals provide a promising

pain-control strategy. Here we present a systematic
review of the published work, reporting on the
effectiveness and toxic effects of systemic radioisotopes
in the management of painful bone metastases.

Physical characteristics of radioisotopes

Although phosphorous-32 was initially used to treat
bone metastases originating from breast and prostate
cancer, the side-effects of myelosuppression reduced its
usefulness. Therefore, this review focuses on strontium89, samarium-153, rhenium-186, and rhenium-188
(table 1). These isotopes are given systemically and are
localised in sites of active bone turnover, which ensures
that all metastases are treated simultaneously. These
isotopes all emit  particles (electrons) with sufciently
long half-lives to provide cytotoxic irradiation of adjacent
malignant cells. 153Sm, 186Re, and 188Re also decay with
 photons, which has the advantage of allowing external
imaging of isotope distribution. Table 2 shows
commonly used doses and pretreatment criteria for
selection of patients for every isotope.
89

Radionuclide

Carrier ligand

Half-life
(days)

 energy
(MeV)

 energy
(MeV)

Maximum range
(mm)

St
Sm
186
Re
188
Re

Chloride
EDTMP
HEDP
HEDP

505
19
38
07

146
081
107
212

0103
0137
0155

70
25
45
110

89

153

EDTMP=ethylenediaminetetramethylene phosphonic acid. HEDP=1-1-hydroethylidene diphosphate.

Table 1: Comparison of the properties of some radioisotopes

individual studies found no dose-response relation, a

retrospective review9 of reported studies found a
substantial positive correlation between rising dose of
89
Sr and complete pain relief. The discrepancy between
these reports could be a result of variable denitions of
response and populations of patients, and of the
inherent difculties in undertaking dose-intensity
studies in patients with severe pain. Moreover, relating
dose to response might not accurately predict tumourtissue exposure and, therefore, response, since a
signicant relation has been reported between the
uptake of 89Sr in malignant skeletal disease on bone scan
and therapeutic response.10

Sr

Strontianite, or strontium carbonate, was rst

discovered in 1790 by Adair Crawford in mineral mines
near the small village of Strontian, Argyll, UK. It was
embedded in samples of barium carbonate, and
Crawford realised that a new element was present in this
ore and named it strontium after the village. A
radioactive form of this element, 89Sr, has now gained
medical importance in the palliation of pain from bone
metastases.
Strontium has the atomic number 38 and is
immediately below calcium in the periodic table of
elements. Not surprisingly, therefore, 89Sr follows the
same metabolic handling in vivo as calcium, and is
readily incorporated into the inorganic matrix of bone.
89
Sr is cleared rapidly from the blood with at least 50% of
the dose localised in skeletal tissue, the uptake being ten
times greater for metastatic tumour lesions than for
healthy bone.5 The concentration in tumour lesions
limits marrow toxicity because the mean range of the
 particle is only 3 mm. 89Sr clearance from plasma is
mainly by renal excretion, with renal clearance varying
from 16 L to 120 L daily.6

Dose-nding studies
Several studies have sought a relation between the dose
activity of 89Sr delivered and the clinical response in
terms of palliation of pain. A study7 assessed the doseresponse relation with doses ranging from 37 Mbq to
1665 Mbq in a mixed population with proven
metastatic disease. No relation was found, and nonresponse was recorded at all doses and for all tumour
types. Another study8 reported no change in pain relief
throughout the range 1530 MBq/kg. Although these
http://oncology.thelancet.com Vol 6 June 2005

Clinical studies of 89Sr

We identied 38 observational studies reporting on the
use of 89Sr for the management of metastatic bone
cancer and 11 randomised controlled trials. Of the
clinical observational studies, 15 recruited 20 patients or
fewer and were excluded, as were ve retrospective
studies and two trials reported in abstract form only. The
remaining 16 studies were prospective. Pain was the
main outcome measure but was assessed by various
methods.8,1024
Most studies used scoring systems, but the differing
criteria used complicate analysis of the data, although
complete response and lack of response are
straightforward to dene. The proportion classied as
complete responders to 89Sr ranged from 8% to 77%,
with a mean value of 32%, and the proportion showing
no response ranged from 14% to 52% (mean 25%).
Within this range 44% of patients had some degree of
response to 89Sr treatment, giving a mean overall
response of 76%. Delay in the start of response was
between 4 days and 28 days, with a response duration of
up to 15 months. Although a reduction in analgesic use
is a major criterion for assessing pain response,
quantication of this variable is poorly reported. In those
studies that did report on this variable, a reduction of
between 71% and 81% was observed.15,17
Response to 89Sr is most effective in patients with
limited skeletal involvement, those with higher
performance status, and those with osteoblastic
lesions.21 89Sr is effective in pain palliation when given in
repeat doses in patients who have a satisfactory response
to the initial dosing,18 although the proportion having a
favourable response to retreatments tends to be
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Review

Radioisotope Dose

Sr-chloride

148 MBq

Sm-EDTMP

37 MBq/kg

Re-HEDP

1295 MBq

Re-HEDP

1144 GBq

89

153

186

188

Schedule

Indications*

Intravenous
12 min;
outpatient
Intravenous
1 min; 4 h
prehydration
and 6 h after
hydration
Intravenous
0550 min
Intravenous
12 min;
inpatient

Platelet
count
(109/L)

White
cell count
(109/L)

Haemoglobin Serum
(g/L)
creatinine
(mol/L)

Karnofsky
Life expectancy
performance (weeks)
status (%)

Prostate, breast, and 60

lung

24

NR

NR

40

Prostate, breast,
lung, and
osteosarcoma

3045

100

13261768 4070

1216

Breast and prostate 100150

34

NR

11491326 4570

1224

Prostate, breast, and 100

lung

34

60

1238

12

100150

4570

NR

*Cancers with several painful, osseous metastases, which are positive on bone scintigraphy. Most studies were done in Germany, where the safety regulations require hospital admission
for up to 2 days. NR= not reported. EDTMP=ethylenediaminetetramethylene phosphonic acid; HEDP=1-1-hydroethylidene diphosphate

Table 2: Commonly used doses and pretreatment criteria for selection of patients

substantially smaller than that for the response to rst

treatment.21 The duration of effect on repeat doses can
also be reduced and possibly reects the reduction in
performance status of patients with advancing disease.19
The toxic effects associated with 89Sr seem to be mild
and reversible. About 15% of patients have increased
pain, are, or after 15 days, which can last for 4 days
and was associated with a good response in one trial.8
Haematological toxic effects are the most commonly
observed side-effects, with a reduction in white-cell
count of 1165% occurring in 1280% of patients.
Platelet counts fall by an average of 29% in 2980% of
patients, whereas red-cell counts change negligibly or
not at all. Generally, blood counts return to normal
values and no intervention is needed. Moreover, some
trials report no substantial change in any haematological
variables associated with 89Sr use.
Trials of hormone-refractory prostate cancer have
reported changes in tumour markers after treatment
with 89Sr. A decrease of more than 50% in serum
prostate-specic antigen was observed in 37% of patients
in one study.20 However, another study12 observed a
mean increase of 36% from the pretreatment
concentration of prostate-specic antigen at 2 months
after
treatment,
although
alkaline-phosphatase
concentrations had decreased by 20%. Many patients
show a reduced intensity of hot spots by bone
scintigraphy compared with pretreatment images,
which, coupled with falling marker concentrations,
suggests a possible tumoricidal effect by 89Sr, although
the evidence is conicting.21
These observational studies, although informative, are
not comparative and do not address the possibility that
elemental strontium itself has an effect or that there is a
placebo effect. This possibility was investigated in a
double-blind, randomised controlled trial of 49 patients
with skeletal metastases from prostatic carcinoma.25
394

Patients were assigned to three injections of 75 MBq 89Sr

with intervals of 1 month (25 patients) or to saline as
placebo. There was no signicant difference in pain
relief between the two groups, which might reect the
suboptimum treatment regimen for 89Sr. However,
survival at 2 years was signicantly better for the 89Sr
group than for the placebo group (046 vs 004,
p=005). Another study randomly assigned 26 patients
with hormone-refractory prostate cancer to 89Sr chloride
or to stable strontium as a placebo.26 This study assessed
response to treatment by scoring the patients general
condition, mobility, analgesic intake, and pain analysis.
89
Sr was substantially more effective than was placebo,
both in patients receiving a single dose (p=001) and in
patients allocated repeat doses (p=003). Furthermore,
complete responses were observed only in patients
receiving radioactive strontium. The absolute risk
reduction for patients achieving pain relief with 89Sr was
0321 (95% CI 0035 to 0678). These studies,
although small, suggest that the therapeutic benet of
89
Sr is not attributable to a placebo effect.

Sr and radiotherapy

89

External radiotherapy has been used for many years to

treat pain associated with metastatic bone cancer. For
discrete foci of metastases, local-eld radiotherapy is
routinely used, but when many lesions are present,
wide-eld radiotherapy, such as hemi-body or wholebody radiotherapy, is more appropriate. Both local-eld
and wide-eld techniques can be associated with
substantial gastrointestinal and haematological toxic
effects, which have prompted the assessment of 89Sr as a
less toxic alternative for controlling pain. In a doubleblind, controlled, randomised trial in Canada, patients
received local-eld radiotherapy and were randomly
assigned 89Sr or saline placebo.27 89Sr was given as a
single injection of 3996 MBq, 25 times that approved
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Review

by the US Food and Drug Administration. There was a

signicant reduction in analgesic use at 3 months in
patients assigned 89Sr, and signicantly fewer new active
sites were recorded with 89Sr. However, groups did not
differ in survival or pain reduction at the index site. A
second placebo-controlled, randomised trial reported
contrasting results.28 That study assessed the
effectiveness of concurrent 89Sr or saline placebo with
palliative external radiotherapy and found no difference
in rates of complete response or progression between
groups, although there was a slight increase in
progression-free survival for patients with prostate
cancer. A third randomised study, done by the European
Organisation for Research and Treatment of Cancer
Genitourinary Group, compared 89Sr with palliative
local-eld radiotherapy in patients with hormonerefractory prostate cancer and found no difference in
subjective response or progression-free survival, but a
signicant increase in survival with local-eld
radiotherapy.29 The toxicity and response rates of 89Sr are
similar when given after local or wide-eld
radiotherapy.30 Comparison of the palliative effect of 89Sr
with external radiotherapy (either local or hemibody)
showed similar responses, and, although fewer new
active sites were recorded in the 89Sr group, there was no
signicant difference in overall survival.31,32
The outcome data presented by these studies for 89Sr
are conicting, although they generally imply similar
subjective response rates to external radiotherapy but
with no improvement in overall survival. Variation in the
denition of efcacy criteria and the differences in the
populations of patients recruited could contribute to the
inconsistencies reported.

Is it possible to improve response to 89Sr?

Early experiments in mice with transplanted tumours
have shown that several cytotoxic drugs can increase the
activity of radiation when combined, with cisplatin and
mitomycin being particularly active.33 Additional
laboratory studies have extended this early work to include
other platinum analogues and microtubule inhibitors
such as paclitaxel. This work has led to strategies to
improve the therapeutic response to 89Sr by giving
concurrent radiosensitisers such as cytotoxic agents.
Sciuto and colleagues34 assessed the effects of low-dose
cisplatin with 89Sr in 70 patients with hormone-refractory
prostate cancer and painful bone metastases in a
prospective, randomised controlled trial. Group A were
assigned to 89Sr and cisplatin and group B to 89Sr alone.
The proportion of patients responding and the duration
of response were signicantly higher with combined
treatment than with 89Sr alone. The same researchers
assessed the use of carboplatin with 89Sr in 30 patients
(23 with prostate cancer and seven with breast cancer) in
a randomised trial,35 and reported a signicantly better
response for combination treatment than for 89Sr alone
(complete response 40% vs 8%). In a further trial,36 103
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patients with hormone-refractory prostate cancer were

treated with intensive induction chemotherapy then
randomly assigned to doxorubicin alone or doxorubicin
plus 89Sr. The results of the study suggested a signicant
improvement in time to progression and survival in
patients assigned strontium. 89Sr combined with
estramustine, vinblastine, mitoxantrone, and hydrocortisone induces a more than 50% fall in the
concentration of prostate-specic antigen in about 50%
of patients.
89
Sr combined with chemotherapy seems to be an
active treatment in the management of metastatic bone
disease, and seems to have a substantial therapeutic
advantage over 89Sr alone.

Comparison of 89Sr with other radioisotopes.

Several studies3740 have compared the efcacy of 89Sr
with other radioisotopes, including 153Sm, 32P, 186Re, and
188
Re in the management of metastatic bone pain.3740
These studies, which included two randomised
controlled trials, reported no signicant difference
between 89Sr and the other radioisotopes in terms of
response rate or toxic effects. A signicant rise in
performance status was noted in patients assigned
188
Re,40 and the duration of response was longer with 89Sr,
although this difference was not signicant. The choice
of radioisotope can therefore be made on the basis of
availability, cost, and clinical preference or experience.
153

Sm

Samarium is a lanthanide with the atomic number 62

and a molecular mass of 15036. 153Sm is prepared by
neutron irradiation of enriched 152Sm2O3.41 Under acid
conditions induced by hydrochloric acid, 153SmCl is
produced, which can then be complexed with the
calcium
salt
of
ethylenediaminetetramethylene
phosphonic acid (EDTMP) to give 153Sm-EDTMP.
In the late 1990s 153Sm was approved in the USA,
Canada, Australia, and Europe for the treatment of pain
from cancer that had spread to the bone. However, the
mechanism by which 153Sm allows palliation of pain is
not fully understood. Chelation of 153Sm with EDTMP
forms a complex that selectively accumulates in skeletal
tissue in association with hydroxyapatite, particularly in
areas where the rate of turnover is high.42 The total
skeletal dose of 153Sm is unpredictable and ranges from
15% to 95%;43 dose measurement is complicated by the
dosimetry of bone-seeking pharmaceuticals. Bone
metastases contain about ve times more 153Sm than
does healthy bone tissue, so malignant cells are
selectively exposed to higher doses of radiation. 153Sm is
cleared rapidly from the blood with a half-life of 55 min
and less than 1% of the dose remaining in the circulation 1 h after administration. Urinary excretion is the
main route of elimination and is complete within 6 h.
Several studies have reported on the toxic effects and
efcacy of increasing doses of 153Sm from 278 to
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Review

1110 MBq/kg4348 The major toxic effect observed was

myelosuppression, with thrombocytopenia being dose
limiting in 2042% of patients. The lowest platelet
counts were delayed (median 34 weeks) but the
decreases were reversible in up to 97% of patients with a
mean recovery time of less than 5 weeks, and
transfusions were needed only at very high doses.46
A transient rise in bone pain (are) after 153Sm was
recorded in 1220% of patients. Palliation of pain was
seen in 7095% of patients and was independent of the
dose given. Two trials43,45 reported a reduction in bonescan intensity in 972% of patients, whereas one trial
reported no change.44
Additional observational studies examining the
therapeutic effect of 153Sm, all report some degree of
pain palliation (from excellent to partial) in 3085% of
patients with mixed tumour sites.4953 Pain relief is
typically noted within 510 days, and this rapid
response is desirable from the patients standpoint, and
can last up to 4 months in some patients. Men with
primary lung cancer, lesions in the vertebra or pelvis,
and concurrent metastases in the legs tend not to
respond to 153Sm.50 Repeat dosing of 153Sm-EDTMP can
improve the duration of pain response and survival.54
Three double-blind, randomised studies41,55,56 have
reported on the efcacy of 153Sm-EDTMP for the
treatment of patients with bone metastases. Resche and
co-workers41 assessed the therapeutic efcacy of two
doses of 153Sm in alleviating metastatic bone pain from
cancers of the prostate (n=76), breast (n=36), lung (n=2),
and a mixed group (n=9). 114 patients were randomly
assigned to 185 MBq/kg or to 37 MBq/kg 153SmEDTMP. All had an improvement in pain assessment,
but those allocated the higher dose responded
signicantly better at 4 weeks than did those allocated
the lower dose (p=004). The proportion able to sleep all
night rose from a baseline of 33% to 45% for those
receiving the lower dose and to 59% for those assigned
the higher dose; the change was signicant at the
higher dose (p=002). Myelosuppression was the only
toxic effect associated with 153Sm, with reductions of
4356% for platelets and 4860% for white cells. Nadirs
were reached at 4 weeks, and both platelet and whitecell counts recovered by 8 weeks. Groups did not differ
in overall survival for patients with prostate cancer, but
patients with breast cancer assigned the higher dose
survived longer than did those assigned the lower dose.
Serani and colleagues55 assessed the efcacy of two
doses of 153Sm-EDTMP versus placebo. 118 patients
with painful metastases secondary to prostate, breast,
or lung cancers were randomly assigned to
185 MBq/kg, 37 MBq/kg, or to placebo. Assessments
of pain intensity by patients and clinicians, were used
to investigate the therapeutic efcacy of 153Sm. An
improvement in pain relief was reported for both
doses compared with the placebo group, but the
improvement was signicantly greater in the
396

37 MBq/kg group than in the 185 MBq/kg group at

4 weeks (67% vs 42%, absolute risk reduction 0256
[95% CI 0043047]). Patients with breast cancer who
were assigned the higher dose seemed to have the
greatest improvement in pain scores. Analgesic
consumption progressively rose in the placebo group
compared with the prestudy rate, whereas there was a
reduction in both active-treatment groups over 4 weeks
after treatment with 153Sm. As in the previous trial, a
mild, transient myelosuppression was the only sideeffect of 153Sm seen in this study. The white-cell count
reached 59% of baseline levels in the 185 MBq/kg
group and 51% of baseline values in the 37-MBq/kg
group, and platelet counts reached 58% of baseline
values in the 185-MBq/kg group and 45% of baseline
values in the 37-MBq/kg group. In both treatment
groups, the counts of white cells and platelets had
recovered by week 8, and only minor changes in
haemoglobin concentrations were recorded in any
group. There were no patients with febrile neutropenia
and no grade 4 toxic effects on white cells or platelets.
The third trial was a phase III, randomised, placebocontrolled study assessed the efcacy of 153Sm-EDTMP
in 152 men with hormone-refractory prostate cancer
and many painful osseous metastases.56 Patients were
assigned 37 MBq/kg samarium lexidronam (153Sm) or
to non-radioactive 153Sm chelated to EDTMP given
intravenously for 1 min with pretreatment and posttreatment hydration. Patients diaries were used to
record analgesic use and metastatic bone pain, which
was assessed with a visual analogue scale and a pain
descriptor scale. At 34 weeks, analgesic consumption
signicantly decreased in patients assigned 153Sm
compared with those assigned placebo (p=005).
Furthermore, both the visual analogue scale and the
pain descriptor scale showed signicant improvements
in the treatment group at 24 weeks, which correlated
with the reduction in analgesic use (p=00004). The
absolute risk reduction for complete responders at 4
weeks was 029 (95% CI 008036). 9% of patients in
the active-treatment group had a greater than 50%
reduction in concentration of prostate specic antigen,
compared with 2% in the placebo group. Mild and
transient myelosuppression was the only clinically
important toxic effect associated with 153Sm. White-cells
counts fell by about 45% and platelet counts fell by
40%, with corresponding nadirs at 34 weeks of
38109/L for the white-cell count and 127109/L for
the platelet count. Normal counts of white cells and
platelets were observed by week 8. Pain ares were
seen in 6% of patients in both groups and were not
associated with increased pain response. Groups did
not differ in overall survival, and the median survival
time was 7 months.
Data from these studies indicate that 153Sm-EDTMP is
effective in reducing pain associated with bone metastases and has a similar toxiceffects prole to that of 89Sr.
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Review

186

Re-HEDP

Re has been assessed in several trials for the

treatment of painful bone metastases, but its use is still
experimental and the isotope is, therefore, not
included in routine treatment. 186Re is complexed with
1-1-hydroethylidene diphosphate (186Re-HEDP), which
bonds to hydroxyapatite crystals by forming hydroxide
bridges in a hydrolysis reaction. This process is
thought to be mediated by the metabolic activity of
osteoclastic cells, and the concentration in bone allows
high doses of 186Re-HEDP to irradiate malignant bone
cells. 86Re-HEDP binds to plasma proteins in a timedependent interaction, and is cleared from the plasma
with a half-life of 41 h. About 70% of the activity is
excreted in the urine within 24 h. The maximum
tolerated activity is 2960 MBq for men with metastatic
prostate cancer and 2405 MBq for patients with breast
cancer, and at therapeutic doses the bone-marrowabsorbed dose is about 104 mGy/MBq.57,58 An early
study by Maxon and co-workers59 used a dose of
12321 MBq 186Re-HEDP and reported an overall pain
response rate of 80%, with a mean duration of 7 weeks
in patients with hormone-refractory prostate cancer. In
that study, pain index, based on a patients log of sleep
patterns, analgesic intake, and pain intensity was the
primary endpoint and a decline of more than 25% was
regarded as a response. Other studies reported similar
overall pain responses of between 38% and 82%, with
186
Re-HEDP doses of 1295 MBq to 1406 MBq.6064
Typically, pain response was delayed by 13 weeks
with a duration of 512 months. There seems to be
no relation between the dose of 186Re-HEDP given
and the overall pain response in the dose range
12952960 MBq.65
A rise in pain intensity or are was recorded in up to
42% of patients, starting 5 days after treatment and
lasting 210 days; it was not related to overall pain
response. The major side-effect with 186Re-HEDP was
haematological, with a fall in platelet count recorded in
up to 36% of patients (grade 2 in 12% and grade 3 in
7%). Grade 2 neutropenia was seen in 29% of patients.
The side-effects continued for about 4 weeks before
returning to baseline, and were rarely clinically
important.
A small trial by Maxon and colleagues66 compared the
efcacy of 1225 MBq 186Re-HEDP with that of placebo,
and found a substantially greater reduction in pain index
with the active drug (40% vs no change). Similar results
were reported by Han and colleagues67 for 111 patients
with hormone-resistant prostate cancer. Mean pain
response was 27% for patients assigned 186Re-HEDP,
compared with 13% for those assigned placebo
(p=005).
These cumulative data suggest that 186Re-HEDP is an
active agent in the palliation of pain associated with bone
metastases, and that haematological toxic effects are
mild and reversible.

Panel: Safety precautions to be taken by patients receiving

radiotherapy and their carers

186

http://oncology.thelancet.com Vol 6 June 2005

Hospital staff
Wear protective shoe covers, gloves, and apron
Work quickly but efciently to reduce exposure
Maintain the greatest distance possible consistent with
care of the patient
Observe rules for handling of blood and urine
Leave soiled items (eg, gloves) in the patients area for
disposal
Wash hands after leaving the patient
Patient
Use a ushable toilet rather than a urinal
Flush toilet twice to reduce environmental contamination
Wipe any spilled urine with a tissue and ush it away
Wash hands after using the toilet
Wash soiled clothes or linen immediately and separately
Wash away spilled blood from cuts
188

Re-HEDP

Re has gained clinical interest for the palliative

management of pain from bone metastases. The
development of the tungsten-188/188Re generator allows
188
Re to be produced easily close to the ward, which is
conducive for clinical research. It can be complexed with
diphosphate ligands such as HEDP (188Re-HEDP). After
dosing, the mean effective biological half-life in bone is
about 16 h, compared with 11 h for bone marrow and
12 h for the whole body.68 About 40% of the activity
received is excreted in the urine within 8 h.
In a dose-escalation study,69 22 men with cancer of the
prostate and painful osseous metastases received a
single dose of 188Re-HEDP ranging from 13 GBq to
44 GBq. Thrombocytopenia was the main side-effect
recorded; the largest decrease in platelet count was 86%
at the highest dose. The maximum tolerated dose was
33 GBq for a baseline platelet count of less than
200109/L and 44 GBq for a baseline platelet count of
more than 200109/L. Pain palliation was reported by
64% of patients and was more frequently seen at the
highest dose.
Despite the ease of production, data for the therapeutic
efcacy of 188Re-HEDP are restricted to four studies.68,7072
These studies recruited a total of 135 patients with mixed
tumour sites and used doses of 1169 GBq. Overall
pain response was seen in 81% of patients (7687%),
and complete response, when analgesics were no longer
needed, was reported in 25%. Pain relief started 18
weeks after treatment and lasted up to 3 months. Pain
are was reported in about 20% of patients, but the
prominent side-effects, as with all the other
radioisotopes, were haematological. Platelet count fell by
an average of 17% (range 025) and the leucocyte count
by 24% (1630); both counts returned to baseline values
by 412 weeks.
188

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In one other study, men with hormone-refractory

prostate cancer were randomly assigned to either one
dose of 188Re-HEDP (407 MBq/kg) or to two doses with
an interval of 8 weeks.73 With a visual analogue scale as
the basis for pain assessment, an overall response of
60% was recorded for the single dosecompred with 92%
for the repeat doses (p=001). Patients assigned repeat
schedule had improved time to progression than did
those assigned one dose (median 7 months vs 23
months, p=001) and overall survival (median 127
months vs 70 months, p=004).

Radiation safety
Radioisotopes are generally given on an outpatient basis,
but in some countries regulations require patients to be
admitted to hospital after being given -emitting
radioisotopes. Radioisotopes are given intravenously and
should only be given by a clinician trained in the use of
unsealed radioactive sources for treatment. Secure
intravenous access, preferably with a exible indwelling
catheter, is essential to avoid extravasation and the
consequences of local tissue damage.  rays can pass out
of the patients body, presenting an external risk to
bystanders; consequently, patients should be treated in
special lead-lined rooms to reduce this hazard. The panel
lists several routine safety measures for hospital staff
and patients relating to radioisotope dosing.
The  particles emitted by radioisotopes bring about
the destruction of malignant cells, but they have a short
range and, therefore, pose little threat to clinicians,
nurses, or family members. A more substantial hazard
arises from the formation of bremsstrahlung X-rays.
These rays are formed by the deceleration of  particles
as they pass through shielding materials, and for this
reason lead is not the best shielding material for
radioisotopes such as 89Sr. Local guidelines for the
handling of radioactive materials should be adhered to
for storage and dosing of radioisotopes, and for dealing
with spillages.
Radioisotopes are mainly excreted in urine, so
precautions must be taken with urine or blood spills.
Patients, their relatives, and hospital staff need to be
informed of the need for care in this respectfor
instance, the proper use of toilets. Incontinent patients
should be catheterised if they are to receive radioisotope
treatment. These precautions are necessary only for the
rst 10 days after treatment when activity in the blood
and urine is greatest.
Concerns about exposure of mortuary or crematorium
staff to radioactivity are unfounded. Schramel and coworkers74 investigated the possible radiation exposure of
pathologists who undertook an autopsy of a patient who
died 4 days after receiving 162 MBq of 89Sr. The
dosimeters worn by the pathology staff read zero at the
end of the procedure. This reading was explained in
terms of the selective distribution of 89Sr to bone and the
low energy of the  particles it emits.
398

Conclusion
There has been increased clinical interest in the
palliative use of radionuclides to treat metastatic bone
cancer, and the data now available provide strong
evidence that they are effective in relieving pain in
substantial numbers of patients.
Most of the studies have recruited patients with
hormone-resistant prostate cancer and more
information is needed on the efcacy of radioisotopes in
other malignant disorders such as breast and lung
cancers. Several studies reviewed did not include
important information, such as the change in analgesic
use, and better and more consistent reporting of clinical
trials is needed. Trials also need sufcient sample size
for the treatment effect to be assessed with adequate
statistical power in a randomised setting.
One of the major drawbacks in investigation of
radioisotopes in patients with bone metastases is the
assessment of bone pain. Pain intensity is a subjective
assessment and is not readily quantiable with
reproducibility between patients and studies. The
variability in assessment of pain response reported in
the published work indicates the need to develop
validated instruments to quantify pain response
accurately and consistently. The use of a unied
instrument in future studies would greatly facilitate
comparative analysis between studies. Furthermore
insufcient consideration has been given to distinguish
the different forms of pain and how they respond to
radioisotopes.4 The development of animal models to
help probe the mechanisms of bone pain might provide
additional data to guide future clinical research.
Some other issues need clarication, such as which
isotope and what schedule to use. All seem to be
effective in reducing bone pain, and have similar toxic
Search strategy and selection criteria
Publications were identied by use of MEDLINE up to the
submission time of this review and dated back to 1966. An
adaptation led to a search of EMBASE, the Cochrane Library,
Science Citation Index, CINAHL, AMED, DARE, and MEDLINE
in Process. Our search strategy consisted of a 25-step search
sequence, starting with thesaurus and text word terms
describing the concept of bone metastases, for example
bone, metastases, osseous, spinal cord,
compression, nerve compression syndromes,
hypercalcaemia, fracture, radioisotopes,
radiopharmaceuticals, and named individual radioisotopes.
There were no language or location restrictions. A search of
the proceedings of the American Society of Clinical Oncology
and the European Conference on Clinical Oncology was done
by hand. The bibliography of each article was used to identify
further relevant studies. Retrospective observational studies,
trials with fewer than 20 patients, and those reported in
abstract form only, were excluded.

http://oncology.thelancet.com Vol 6 June 2005

Review

effects proles; therefore the cost and ease of

preparation will be the deciding factors. However,
comprehensive and up to date cost analyses will be
needed. When radioisotope treatment should be started
and which categories of patients will probably respond
are also not clear. These questions need further
investigation if the full clinical benet of radioisotopes is
to be established.
Acknowledgments
We thank Bernadette Coles for developing and running the search
strategies for this review, and the following people for their time and
effort in translations: Wai Man Zse, Pat Harnden, and the nal-year
medical students from the Tokyo Womens University, Tokyo, Japan, on
elective placement at Cardiff University, Cardiff, UK.
Conict of interest
We declare no conicts of interest.
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