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 CŠ=ðplasma creatinine 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.
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