European Nuclear Medicine Guide
Radiopharmaceutical: [153Sm]Samarium-ethylenediaminetetramethylene phosphonic acid ([153Sm]Sm-EDTMP, Quadramet®, Samarium (153Sm) lexidronam-Pentanatrium) [53].
Nuclide: Samarium-153 emits β particles with maximum energies of 0.81 MeV (20%), 0,71 MeV (30%), 0,64 MeV (50%) mean energy of 0.23 MeV, average soft tissue range of 0.6 mm and γ photons with a 0.103-MeV photo peak (28%). The physical half-life is 46.4 h.
Standard administered activity per body weight: 37 MBq/kg
Administration: [153Sm]Sm-EDTMP is supplied frozen as a sterile isotonic solution for intravenous (i.v.) administration.
Samarium is a lanthanide and as [153Sm]Sm3+ makes a complex with the tetraphosphonate EDTMP, which has a high affinity for hydroxyapatite in bone in vivo. Following intravenous administration, ([153Sm]Sm-EDTMP is quickly taken up by bone, and preferentially by bone metastases with an average metastasis-to-normal bone ratio of 5:1. Median value of the urinary excretion is 40 (range: 3-75) % of the administered activity [58].
The percentage depends on the degree of skeletal metastasis; the greater the number of metastases, the less ([153Sm]Sm-EDTMP is excreted. Likewise, the amount of ([153Sm]Sm- EDTMP taken up in the skeleton depends on the extension of metastasis. This is a highly relevant factor for possible toxicity, which is related to (or influenced by) the amount of ([153Sm]Sm-EDTMP taken up by the skeleton.
Patients eligible for treatment should meet the following conditions:
Absolute contraindications:
Relative contraindications:
In general, in these cases there is an increased risk of haematological adverse reactions such as neutropenia and thrombocytopenia. This situation includes patients with evidence of compromised bone marrow reserve, e.g. following prior cytotoxic chemotherapy and/or radiation treatment (such as extensive external beam radiation therapy, EBRT) or in patients with advanced diffuse metastatic infiltration of the bone demonstrated by a “superscan” pattern at bone scintigraphy. These patients should be treated only after careful clinical risk–benefit assessment and close monitoring is necessary. Moreover, therapy with bone-seeking radiopharmaceuticals could not be the best option recommended in these situations, since valid data on overall efficacy are not available.
A relatively low blood cell count, within certain limits, may be a relative contraindication to radionuclide bone treatment because of possible myelotoxicity. Nevertheless, the precise lower limit is not well defined in the literature and the use of granulocyte colony-stimulating factors may further lower the limit.
The following cell count limits should be applied:
The presence of bone marrow involvement does not represent an absolute contraindication, but the blood values should remain within the cited limits and the extent of substitution should not exceed a threshold above which severe myelotoxicity is expected.
Blood cell counts should be stable before undertaking bone palliation therapy. If there is any doubt or delay in performing the therapy due to low blood cell counts, it might be worthwhile repeating blood sampling just before the treatment to exclude rapid deterioration in blood cell counts before administration of the therapeutic radionuclides.
The facilities required will depend on the national legislation for the emission of β-γ emitting therapy agents.
The patient should be well-hydrated beforehand. [153Sm]Sm-EDTMP is administered as a bolus through a free running drip using a syringe protected with a lead shield.
Haematological values should be checked every two weeks following therapy to see whether thrombocyte levels have returned to normal (after approximately 8 weeks). The first outpatient follow-up appointment should be scheduled three weeks after treatment and should include a blood test to check thrombocyte level. The patient should be seen again one week later if the thrombocyte level is significantly low (maximum drop in thrombocyte count).
Follow-up nuclear medicine appointments should be scheduled in close collaboration with the patient’s lead specialist. Regarding patients who die shortly following treatment, cremation is not considered to pose an unacceptable radiation hazard (crematorium staff can be exposed to doses of up to approximately 1 µSv) but this may vary according to national legislation.
Contraception should be used for 4 months following treatment. [153Sm]Sm-EDTMP can be administered on an out-patient basis, and there are no restrictions on normal interactions with friends or relations
Incontinent patients should be catheterized before radiopharmaceutical administration for the radioprotection of relatives and/or carers. The catheter should remain in place for 24h.
Tumour absorbed doses evaluated by planar dosimetry in seven patients treated with 222 MBq/kg of [153Sm]Sm-EDTMP varied from 2 Gy to 66 Gy (median 25 Gy) [59]. Results based on state-of-the-art voxel dosimetry (3D SPECT/CT dosimetry) in another group of patients indicated a range of 3-60 Gy of mean tumour absorbed doses for the same activity of 222 MBq/kg [60]. Absorbed doses per administered activity (mGy/MBq) of [153Sm]Sm-EDTMP evaluated in a group of 7 patients to normal organs, given as median values (range), are: bone surfaces: 6,4 (5,3 -8,8); red marrow: 1,5 (1,2-2,0); urinary bladder wall: 1,2 (0,4-1,3). Negligible values (< 0,04 mGy/MBq) were found for other organs [61]. The red marrow absorbed dose evaluated in 41 patients ranged between 2.0 Gy and 4.7 Gy (mean value ± 1SD of 3.5 ± 0.7 Gy) in patients treated with 37 MBq/kg [62].
For recurrent pain in an area which has been previously irradiated, repeat external irradiation is often contraindicated especially for the risk of osteonecrosis. Therapeutic bone-seeking radiopharmaceuticals used at an earlier stage represent a valid option for painful bone metastases. The effectiveness of these pharmaceuticals is comparable to that of external radiotherapy, involves relatively mild toxicity and is relatively patient-friendly. Randomized, placebo-controlled trial have been shown that [153Sm]Sm-EDTMP is an effective pain treatment in patients with multifocal, painful bone metastases with pain relief reported in approximately 30 % of cases [63,64].
For [153Sm]Sm-EDTMP, a significant dose-response relationship for transient tumour volume shrinkage has been reported [60].
No comparative studies have yet been carried out to compare the effectiveness of [153Sm]Sm-EDTMP with that of other radiopharmaceuticals such as [188Re]Re-HEDP and [89Sr]SrCl2. To be noticed that external radiotherapy (or even neurosurgery) is always preferable in patients with myelocompression or threatened/current neurological deficit.
In case of persistent pain, retreatment can be effective and safe, if haematological parameters are fully recovered from the previous one, although the entity of response may decrease with the number of treatments. For [153Sm]Sm-EDTMP The minimum delay between two treatments should be of 8 weeks [53].
Toxicity is limited mainly to reversible bone marrow depression which manifests as a temporary drop in thrombocyte and leucocyte levels and reaches its lowest point in the fourth week following therapy [61]. Recovery often occurs within 6-8 weeks.
The red marrow absorbed dose estimated by SPECT/CT has been shown to be predictive of myelotoxicity for treatment with [153Sm]Sm-EDTMP [65].
Red marrow dosimetry showed a low correlation with the maximum decrease in leukocyte counts, and with the maximum drop in platelet counts [66].
Properly rescaled dosimetry using patient specific parameters and SPECT/CT has shown to improve the prediction of myelotoxicity for treatment with [153Sm]Sm-EDTMP. Platelets (PLT) and White Blood Cells (WBC) levels were correlated with red marrow absorbed doses, and ROC curves yielded toxicity thresholds of 2.6 Gy for PLT and 2.3 Gy for WBC [65].
A temporary ‘flare response’ (increase in pain) can sometimes occur (in approximately 10% of cases). This usually lasts 24-72 h and is often followed by a good response to treatment.
[153Sm]Sm-EDTMP is approved for pain reduction as supportive care for symptomatic bone metastases from prostate cancer and other osteoblastic malignancies.