Eanm procedure guideline for treatment of refractory metastatic bone pain
Eur J Nucl Med Mol ImagingDOI 10.1007/s00259-008-0841-y
EANM procedure guideline for treatment of refractorymetastatic bone pain
Lisa Bodei & Marnix Lam & Carlo Chiesa & Glenn Flux &Boudewijn Brans & Arturo Chiti &Francesco Giammarile
the use of bone-seeking radiopharmaceuticals. The purpose of
Introduction Bone pain is a common symptom of meta-
this guideline is to assist the nuclear medicine physician in
static disease in cancer, experienced with various intensities
treating and managing patients undergoing such treatment.
by about 30% of cancer patients, during the development oftheir disease, up to 60–90% in the latest phases.
Keywords Guidelines . Nuclear medicine .
Discussion In addition to other therapies, such as analgesics,
Bone palliation . 89Sr . 153Sm-lexidronam . 186Re-etidronate
bisphosphonates, chemotherapy, hormonal therapy andexternal beam radiotherapy, bone-seeking radiopharma-ceuticals are also used for the palliation of pain from bone
metastases. Substantial advantages of bone palliation radio-nuclide therapy include the ability to simultaneously treat
The purpose of this guideline is to assist nuclear medicine
multiple sites of disease with a more probable therapeutic
effect in earlier phases of metastatic disease, the ease ofadministration, the repeatability and the potential integration
1. Evaluating patients who might be candidates for treat-
ment to palliate refractory, metastatic bone pain using
Conclusion The Therapy, Oncology and Dosimetry Commit-
89Sr (approved in Europe for prostate cancer), 153Sm-
tees have worked together to revise the EANM guidelines on
lexidronam (153Sm-EDTMP; approved in Europe for
Nuclear Medicine Division, European Institute of Oncology,
M. LamDepartment of Radiology and Nuclear Medicine,University Medical Center Utrecht,
U.O. di Medicina Nucleare,Istituto Clinico Humanitas,
Department of Nuclear Medicine, Istituto Nazionale dei Tumori,
G. Flux“Royal Marsden NHS Trust and Institute of Cancer Research”
osteoblastic metastases) or 186Re-etidronate (186Re-
Bone-seeking radiopharmaceuticals may be also
HEDP; approved in some European countries).
used for the treatment of primary and metastatic bone
2. Providing information for performing these treatments.
tumours, such as osteosarcoma, inducing an osteoblastic
3. Understanding and evaluating the consequences of
Bone-seeking radiopharmaceuticals are one of the therapeutictools available for palliation of bone pain and should be used
Bone pain is a common symptom of metastatic disease in
within a multidisciplinary approach to choose the best option
cancer, experienced with various intensities by about 30% of
for each patient in a correct sequence.
cancer patients, during the development of their disease, up to
A careful patient selection should be performed before
60–90% in the latest phases . In addition to other therapies,
treatment with bone-seeking radiopharmaceuticals, which
such as analgesics, bisphosphonates, chemotherapy, hor-
should be preferably administered early in the metastatic
monal therapy and external beam radiotherapy, bone-seeking
phase, to increase the rate of therapeutic responses. Haema-
radiopharmaceuticals are also used for the palliation of pain
tological function at peripheral blood cell count, bone
from bone metastases. Substantial advantages of bone
(marrow) involvement at pre-therapy bone scintigraphy,
palliation radionuclide therapy include the ability to simul-
performance status, recent use of myelosuppressive thera-
taneously treat multiple sites of disease with a more probable
pies, and expectancy of life should be considered before
therapeutic effect in earlier phases of metastatic disease, the
ease of administration, the repeatability, and the potentialintegration with the other treatments.
1. 89Sr emits a beta particle with a maximum energy of
1.46 MeV, mean energy of 0.58 MeV, average soft-
tissue range of 2.4 mm and 0.01% abundant gammaemission with a 0.91-MeV photo peak. The physicalhalf-life is 50.5 days .
1. Metastatic bone pain in this context means bone pain
2. 153Sm emits a beta particle with a maximum energy of
arising from secondary skeletal malignancy.
0.81 MeV, mean energy of 0.23 MeV, average soft-
2. Bone palliation means conventionally the treatment of
tissue range of 0.6 mm and a 28% abundant gamma
metastatic bone pain resistant or intolerant to conventional
emission with a 0.103-MeV photo peak. The physical
treatments such as analgesics, bisphosphonates, anti-
tumour therapy (chemotherapy or hormone manipulation)
3. 186Re emits a beta particle with a maximum energy of
or arising from multiple sites not easily controlled by
1.07 MeV, mean energy of 0.349 MeV, average soft-
external beam radiotherapy or surgery.
tissue range of 1.1 mm and a 9% abundant gamma
3. Radionuclide therapy in this context means the intrave-
emission with a 0.137-MeV photo peak. The physical
nous administration of 89Sr-chloride in aqueous solution,
or 153Sm-lexidronam (153Sm-ethylene-diamine-tetra-methylene-phosphonate [EDTMP]), or 186Re-etidronate(186Re-hyroxyethylidine-diphosphonate] [HEDP]).
4. Bone-seeking radiopharmaceuticals efficacy relies on
their selective uptake and prolonged retention at sites ofincreased osteoblastic activity. The exact mechanism of
Intravenous injection of 89Sr-chloride, 153Sm-lexidronam or
action is not fully understood, but involves the reduction
186Re-etidronate is used for the treatment of bone pain due
of cytokines and growth factors released by tumour and
to osteoblastic metastases or mixed osteoblastic lesions
inflammatory cells at the interface between tumour and
from prostate or breast carcinomas (established indications)
normal bone and radiation-induced mechanical factors,
or any other tumour presenting osteoblastic lesions seen as
such as reduction of periosteal swelling [
areas of intense uptake at bone scan.
5. Osteoblastic means focal increased skeletal metabolic
Approval for the clinical use of radiopharmaceuticals may
activity, namely, sclerosis, caused by osseous reaction
vary in different countries. The choice of the radiopharma-
to bone metastases, as evidenced by increased activity
ceutical is based on the physic characteristics of the
on bone scintigraphy. Osteolytic means focal areas of
radionuclide in relation to the extent of metastatic disease,
bone destruction caused by the action of osteoclasts. A
the bone marrow reserve and the availability of the
mixed pattern, however, is common in many lesions
case, 153Sm-lexidronam and 186Re-etidronate are the treat-ments of choice. Repeated treatment in the case of acceptable
toxicity must be considered after 8 weeks ,
89Sr, 153Sm-lexidronam and 186Re-etidronate have no
Relative Low blood cell count, within certain limits, may
place in the management of acute spinal cord compression
represent a relative contraindication to the use of bone-
or in treating pathological fractures. Metastases at risk of
seeking radiopharmaceuticals for the possible myelotoxicity.
such complications should be appropriately evaluated on
Nevertheless, the precise lower limit is not well-defined in
the basis of clinical and neurological symptoms, examina-
literature and the use of granulocyte CSFs may lower further
tion and, if necessary, radiology. In particularly selected
the limit. Routinely, the following values can be considered
cases, “chronic” spinal cord compression can be evaluated
for radionuclide therapy, together with high-dose cortico-steroid administration and a careful clinical observation
2. Total white cell count <3.5×109 l−1,
Therapy with 89Sr, 153Sm-lexidronam or 186Re-etidronate
3. Platelet count <100×109 l−1.
is inappropriate for patients with a life expectancy less than4 weeks and, considering the latency in the onset of the
In selected situations, however, lower values can be
palliative effect, is more beneficial in patients with a
considered: values of WBC ≥2.4×109 l−1 may be used;
values of PLT, such as ≥60×109 l−1, can be considered,provided that chronic disseminated intravascular coagu-lation (DIC) can be excluded by means of coagulation
The presence of bone marrow involvement does not
represent per se a contraindication, provided that bloodfigures remain within the cited parameters and the extent of
The facilities required will depend on the national legisla-
substitution does not trespass a threshold beyond which
tion for the emission of pure beta- or beta–gamma-emitting
severe myelotoxicity is expected. Bone scintigraphy may
therapy agents. If in-patient treatment is required by
help to describe the extent of bone marrow involvement.
national legislation, this should take place in an approved
Usually a superscan appearance on bone scintigraphy
facility with appropriately shielded rooms and en-suite
corresponds to an important bone marrow involvement
and this represents a contraindication, except for selected
The facility in which treatment is administered must have
situation in which bone marrow figures are within limits.
appropriate personnel, radiation safety equipment, proce-
Blood cell figures should be stable before undertaking
dures available for waste handling and disposal, handling of
bone palliation therapy. If there are any doubts to perform
contamination, monitoring personnel for accidental contam-
the therapy due to low blood cell counts, it might be
ination and controlling contamination spread [
worthwhile to repeat with a new blood sample within a
The administration of 89Sr, 153Sm-lexidronam or 186Re-
short time frame to exclude a rapid deterioration in blood
etidronate should be undertaken by appropriately trained
medical staff with supporting physics and nursing staff.
Poor renal function reduces the plasma clearance of
Physicians responsible for treating patients should have
bone-seeking radiopharmaceuticals, thus leading to a higher
an understanding of the clinical pathophysiology and
whole-body dose and risk of myelotoxicity. Therefore,
natural history of the disease processes, should be familiar
patients with severely reduced renal function: creatinine
with other forms of therapy and should be able to liaise
>180 μmol/l and/or GFR <30 ml/min should be excluded.
closely with other physicians involved in managing the
The safety and toxicity of treatment in patients with
renal insufficiency has not been thoroughly investigated.
Clinicians involved in unsealed source therapy must be
However, an increase of myelosuppressive toxicity is
knowledgeable about and compliant with all applicable
expected because of the impairment of renal excretion. It
national and local legislation and regulations.
is, therefore, advised to lower the administered dose by50% in patients with creatinine clearance <50 ml/min
(according to the Cockroft and Gault formula forcreatinine clearance in ml/min: ð
Patients considered for 89Sr, 153Sm-lexidronam or 186Re-
ðkgÞ Â C=ðplasma creatinineÂ 0:814Þ in which C=1 if
etidronate therapy will have pain that limits normal activities
male, C=0.85 if female; plasma creatinine in μmol/l). In this
and/or is not easily controlled by regular analgesics. Patients
may have failed conventional analgesics, bisphosphonates
Patients should be warned of the risk of temporary
and anti-tumour therapy (chemotherapy, hormone manipu-
lation), but better candidates to bone-seeking radiopharma-
The patient should be told that pain reduction is unlikely
ceuticals, to obtain a better response, are those in earlier
within the first week, more probable in the second week
and could occur as late as 4 weeks or longer after injection,
Patients will have undergone recent (within 4 weeks or
particularly for long-lived isotopes. Patients should contin-
less) bone scintigraphy documenting increased osteoblastic
ue prescribed analgesics until bone pain decreases and
activity at painful sites. Radiographs demonstrating osteo-
receive advice regarding subsequent analgesic dose reduc-
sclerotic lesions are inadequate, as increased bone density
does not always result in increased uptake on radionuclide
Patients should also be informed on the duration of
imaging. Abnormalities on bone scintigraphy must be
the analgesic effect, generally of 2–6 months and that re-
correlated with appropriate physical examination to exclude
other causes of chronic pain, which would be unlikely to
The patient should understand that 89Sr, 153Sm-lexidronam
respond to treatment using bone-seeking radiopharma-
or 186Re-etidronate are palliative treatments especially
ceuticals. Neurogenic pain and pathological fractures should
designed for treating bone pain and are unlikely to cure
Clinical practice and experimental studies demonstrated
that treatment can be safely performed after local field external
beam radiotherapy. The use of wide field (hemi-body)radiotherapy within 3 months of 89Sr, 153Sm-lexidronam or
89Sr, 153Sm-lexidronam and 186Re-etidronate are supplied
186Re-etidronate administration is likely to result in increased
in solution to be used at room temperature. 89Sr, 153Sm-
myelosuppression and is relatively contraindicated [–].
lexidronam and 186Re-etidronate should be administered by
Except for experimental clinical trials exploring the anti-
slow infusion via an indwelling intravenous butterfly or
tumour potential of combined chemotherapy and bone-
cannula followed by 0.9% saline flush. Care should be
seeking radiopharmaceuticals, long-acting myelosuppressive
taken to avoid extravasation of the radiopharmaceutical.
chemotherapy should be discontinued at least 4 weeks before
Recommended administered activities are as follows:
the administration of 89Sr, 153Sm-lexidronam or 186Re-
etidronate and withheld for 6–12 weeks post-therapy to
avoid concomitant myelosuppression [, ].
A full haematological and biochemical profile should be
obtained within 7 days of proposed treatment. Recommended
The use of bone-seeking radiopharmaceuticals is associ-
reference levels are listed in Section .
ated with improved pain control and decreased analgesic
DIC may be a risk factor for severe thrombocytopenia
consumption. To evaluate the therapeutic effect, patients
post-therapy. Pre-treatment clotting studies to identify
should be monitored by means of objective parameters,
patients with subclinical DIC should be performed ].
such as the visual analogue scale or quality of life
There are conflicting data as to whether bisphospho-
assessment forms or the course of analgesic intake.
nates inhibit the uptake of radiolabelled phosphonates in
Important differences between the radiopharmaceuticals
bone metastases. This discussion is based on the hypoth-
are physical half-life, energy of gamma emission and beta
esis that as both drugs interact at the hydroxyapatite
emission. These differences determine both the clinical
crystal surface of the skeleton, competition might exist for
benefit and the side effects. Although no clear difference in
uptake by bone. At present, there is no evidence of
treatment response between 89Sr, 153Sm-lexidronam and
competition between bisphosphonates and 153Sm-lexidronam,
186Re-etidronate was reported, differences in onset of
186Re-etidronate or 89Sr. Therefore, they may be used
response, duration of response and toxicity do exist. The
onset of response is rapid after treatment with short-livedisotopes (i.e. 153Sm-lexidronam and 186Re-etidronate).
After treatment with long-lived isotopes (89Sr), the onsetis prolonged for a few weeks. The duration of response, on
Patients should receive both written and verbal information
the other hand, is longer for long-lived radioisotopes than
about the procedure before receiving therapy. Informed
written consent must be obtained from the patient, if
Patients with progressive disease and pain, for whom
rapid relief is warranted, are best treated with short-lived
Patients should be told that 60–80% of patients benefit
isotopes. Relief will be quick and toxicity acceptable If
from 89Sr, 153Sm-lexidronam or 186Re-etidronate therapy.
needed, patients can be re-treated. Patients with a somewhat
better prognosis and better clinical condition may be treated
Because urinary excretion of 153Sm-lexidronam and
with long-lived isotopes. The duration of response will be
186Re-etidronate is fast and takes place predominantly during
longer. However, care must be taken for myelosuppressive
the first 8–12 h after injection, special caution for urinary
contamination should be taken during this first period.
In responding patients, in case of recurrent pain, re-
Incontinent patients should be catheterised before radio-
treatment can be effective and safe, provided that haemato-
pharmaceutical administration for radioprotection of rela-
logical parameters are fully recovered, although the quality
tives and/or caring personnel. The catheter should remain in
of response may decrease with treatments. The minimum
place for an appropriate period of time (89Sr=4 days, 186Re-
should be of 8 weeks for 153Sm-lexidronam, 6–8 weeks for
etidronate=2–3 days, 153Sm-lexidronam=24 h). Catheter
bags should be emptied frequently. Gloves should be worn
Starting from the observation of biochemical response
by staff caring for catheterised patients.
reported on tumour and bone resorption markers, presently,
If in-patient treatment is required, nursing personnel
multiple phase I/II studies are focussing on the tumouricidal
must be instructed in radiation safety. Any significant
effect of the combination of radiosensitising chemothera-
medical conditions should be noted and contingency plans
peutic agents and bone-seeking radiopharmaceuticals
made in case radiation precautions must be breached for a
, ]. In this case, the different physical properties of
medical emergency. Concern about radiation exposure
each radiopharmaceutical will influence on the toxicity
should not interfere with the prompt appropriate medical
profile of the particular combination ].
At the moment, signals from literature indicate that,
Haematological toxicity is the main side effect of bone-
despite the fact that a conclusive statement is not possible
seeking radiopharmaceuticals. Therefore, periodical haemato-
to date, the use of bone-seeking radiopharmaceuticals may
logical monitoring may be useful up to 6 weeks post-therapy
improve survival especially when used in earlier phases of
(153Sm-lexidronam, 186Re-etidronate) to exclude significant
metastatic disease or in combination with chemotherapy or
myelosuppression in high-risk patients. After treatment with
89Sr, longer follow-up is necessary because of prolongedmyelosuppressive toxicity (12–16 weeks) .
Post-therapy scintigraphy, when feasible, may be of
value to check tumour extent and radiopharmaceutical
The treating clinician must advise the patient on reducing
distribution and to perform dosimetry calculations.
unnecessary radiation exposure to family members and thepublic.
Following treatment, patients should thoroughly avoid
pregnancy for at least 6 months after 153Sm-lexidronam and
“Flare” phenomena: increase of pain symptoms, in about
186Re-etidronate, and even longer for 89Sr. In reality, it is
10% of the patients, usually within 72 h, typically transient,
unlikely that women of childbearing age will be eligible for
usually mild and self-limiting and usually responding to
standard analgesics. Generally, flare phenomena are asso-
Patients should be appropriately hydrated before and
ciated with good clinical response [, , , ].
after therapy. If the treatment is performed on an out-patient
When cervicodorsal spinal metastases are present, an
basis, patients should remain in the nuclear medicine
increase rate of spinal cord compression is possible.
facility for the first 4–6 h after administration.
Prophylactic corticosteroids may be considered according
Urinary radiopharmaceutical excretion is of particular
concern during the first 2–3 days post-administration, partic-
A decrease of thrombocytes and leucocytes count in
ularly for 89Sr. Urinary excretion of 186Re-etidronate takes
peripheral blood, as a result of myelosuppression, is
place mostly during the first 24 h after administration. For
frequently observed and has a nadir of 3–5 weeks (153Sm-
153Sm-lexidronam, it is nearly completed after the first 8–12 h
lexidronam, 186Re-etidronate) or 12–16 weeks (89Sr). The
after administration. Patients should be advised to observe
occurrence of grade 3 or 4 toxicity is dependent on previous
rigorous hygiene to avoid contaminating groups at risk using
(myelosuppressive) therapy and bone marrow disease.
the same toilet facility. Patients should be warned to avoid
Haematological toxicity is usually temporary with complete
soiling underclothing or areas around toilet bowls for 1 week
or partial recover over the next 3 months. The rate of
post-injection and that significantly soiled clothing should be
recovery depends on the administered activity and the bone
washed separately. A double toilet flush is recommended
after urination. Patients should wash their hands after
Calcium-like flushing sensation, described with the
urination. If contaminated with urine, patients should wash
use of 89Sr, should not occur if the compound is infused
their hands abundantly with cold water without scrubbing ].
2. Use a dose calibrator specially configured to quantify
1. Pharmaceutical name: 89Sr-strontium-chloride
Labelling: The radiopharmaceutical is supplied in aque-
1. Beneficial effect of combined treatment, such as
chemotherapy with bone-seeking radiopharmaceuticals,
2. Beneficial effects of bone-seeking radiopharmaceuticals
in patients receiving bisphosphonates concomitantly.
3. Safety of bone-seeking radiopharmaceuticals in patients
with extensive bone marrow substitution (“superscan”
2. Pharmaceutical name: 153Sm-samarium-lexidronam
Labelling: The radiopharmaceutical is supplied in aque-
The European Association of Nuclear Medicine has written
and approved guidelines to promote the cost-effective useof high-quality nuclear medicine therapeutic procedures.
These generic recommendations cannot be rigidly applied
to all patients in all practice settings. The guidelines should
not be deemed inclusive of all proper procedures or
exclusive of other procedures reasonably directed to
obtaining the same results. Advances in medicine occur at
a rapid rate. The date of a guideline should always be
considered in determining its current applicability.
3. Pharmaceutical name: 186Re-rhenium-etidronate (HEDP)
Labelling: The radiopharmaceutical is supplied in aqueous
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Volume 21, Number 4, 2011ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2010.0403Radiation Safety in the Treatment of Patientswith Thyroid Diseases by Radioiodine 131I: PracticeRecommendations of the American Thyroid AssociationThe American Thyroid Association Taskforce on Radioiodine SafetyJames C. Sisson,1 John Freitas,2 Iain Ross McDougall,3 Lawrence T. Dauer,4 James R. Hurley,5James D. Brier
SIMPSON CENTRE FOR REPRODUCTIVE HEALTH ROYAL INFIRMARY of EDINBURGH Clinical Protocol DIABETES IN PREGNANCY Diabetes; Management of GlycaemicControl in labour and in the antenatal period. Document Information Diabetes: management of glycaemic control. Current clinical guideline for glycaemic control in women with diabetes in labour and in the antenatal period. MANAGEMENT