European Nuclear Medicine Guide
Rhenium-186 and Rhenium-188 have been used in some European countries for pain reduction as supportive care for symptomatic bone metastases from prostate cancer and other (osteoblastic) malignancies based. At this moment their use is limited related to both unavailability and/or upcoming of other radionuclides.
Radiopharmaceutical: [186Re]Rhenium-HEDP, Rhenium (186)-etidronate ([186Re]Re-HEDP) (1).
Nuclide: Rhenium-186 emits a β particle with a maximum energy of 1.07 MeV, mean energy of 0.349 MeV, average soft tissue range of 1.1 mm, and a 9% abundant γ emission with a 0.137 MeV photo peak. The physical half-life is 3.7 days.
Activity: Recommended administered activity is 1.295 MBq.
Administration: [186Re]Re-HEDP is supplied in aqueous solution and administered by intravenous slow infusion.
Radiopharmaceutical: [188Re]Rhenium-HEDP ([-188Re]Re-HEDP)-Hydroxyethylidenediphosphonate (188Re-HEDP)
Nuclide: Rhenium-188. It emits high-energy beta particles with a maximal energy of 2.1 MeV and half-life of 17 hours.
Activity: 2960-3700 MBq
Administration: [188Re]Re-HEDP is administered as a bolus injection (using a lead syringe shield) through a free running drip.
Rhenium is a transition metal and similarly to Technetium-99m makes a complex with the bisphosphonate HEDP (editronate), which has a high affinity for hydroxyapatite in bone in vivo.
Rhenium-186 and Rhenium- 188 distribute rapidly in by bone metastases with high osteoblastic activity and present a prevalent urinary excretion.
Patients eligible for treatment should meet the following conditions:
• Skeletal scintigraphy which shows uptake of bisphosphonate in multiple skeletal metastases
-Absolute contraindications:
Pregnancy, breastfeeding.
Pain in conjunction with a neurological deficit due to metastatic invasion (urgent local external beam radiotherapy is then indicated).
-Relative contraindications:
The facilities required will depend on the national legislation for the emission of β-γ emitting therapy agents.
Patients will have undergone recent (within 4 weeks or less) bone scintigraphy documenting increased osteoblastic activity at painful sites.
The use of wide field (hemi-body) radiotherapy within 3 months of [186Re]Re-HEDP administration is likely to result in increased myelosuppression and is relatively contraindicated.
Long-acting myelosuppressive chemotherapy should be discontinued at least 4 weeks before the administration of [186Re]Re-HEDP and withheld for 6-12 weeks post-therapy to avoid concomitant myelosuppression.
Patients should be appropriately hydrated before and after therapy particularly in patients with poor renal function.
A full haematological and biochemical profile should be obtained within 7 days of proposed treatment. Disseminated Intravascular Coagulation (DIC) may be a risk factor for severe thrombocytopenia post-therapy. Pre-treatment clotting studies to identify patients with subclinical DIC should be performed. The first outpatient follow-up appointment should be scheduled 3 weeks after the treatment. In the event of a significant reduction in thrombocytes, the patient should return for weekly follow-up appointments until the thrombocyte level has returned to normal.
There are conflicting data as to whether bisphosphonates inhibit the uptake of radiolabelled phosphonates in bone metastases. At present, there is no evidence of competition between bisphosphonates and [186Re]Re-HEDP.
[186Re]Re-HEDP and [188Re]Re-HEDP are excreted mainly through the urine. The urinary excretion is fast and takes place predominantly during the first 12–24 hours after injection, special caution for urinary contamination should be taken during this first period. Incontinent patients should be catheterized before radiopharmaceutical administration for radioprotection of relatives and/or caring personnel.
The patient should be instructed to use adequate contraception for the four months following treatment. Patients should not become pregnant for at least 6 months after administration of [186Re]Re-HEDP.
Regarding patients who die shortly following treatment, cremation is usually not considered to pose an unacceptable radiation hazard (crematorium staff can be exposed to doses of up to approximately 1 µSv) but this varies according to national legislation.
In a Phase I/II trial evaluating SPECT/CT based whole body and lesion dosimetry in 22 patients with bone metastases from castration resistant prostate cancer receiving 5 GBq of [186Re]Re-HEDP the mean absorbed per patient dose was 19 (±6) Gy and the mean whole-body absorbed dose was 0.33 (±0.11) Gy. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Patient mean absorbed dose correlate was demonstrated to be a prognostic factor for OS in univariate analysis but not at multivariable analysis [67].
The absorbed doses for [186Re]Re-HEDP to relevant organs by physiological uptake are for bone surface 1.4 mGy/MBq, for red bone marrow 1.3 mGy/MBq, for lower bowel wall 0.57 mGy/MBq, bladder 0.54 mGy/MBq, testes 0.008 mGy/MBq, ovaries 0.019 mGy/MBq, kidneys 1.5 mGy/MBq.
For [188Re]Re-HEDP in patients with bone metastases, the average calculated absorbed dose (mGy/MBq) is 0.6 in red marrow, 0.71 in the kidneys, 0.07 in the whole body, and 3.8 in the bone metastases. Hence 3000 MBq correspond to 1.8 Gy in the bone marrow and 11.4 Gy in the bone metastases [68].
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.
‘A randomized, placebo-controlled trial has been shown that Re-186 HEDP is an effective pain treatment in patients with multifocal, painful bone metastases [69].
A pain relief from [186Re]Re-HEDP therapy can be achieved in 60-80% of cases. Patients should be warned of the risk of temporary increase in bone pain (flare phenomenon). The patient should be told that pain reduction is unlikely within the first week, more probable in the second week and could occur as late as 4 weeks or longer after injection.
In responding patients, in case of recurrent pain, retreatment can be effective and safe, if haematological parameters are fully recovered, although the entity of the response may decrease with treatments. The minimum time before retreatment should be at least 6-8 weeks.
Haematological toxicity is the main side effect of bone seeking radiopharmaceuticals. Therefore, periodical haematological monitoring may be useful up to 6 weeks post-therapy to exclude significant myelosuppression in high-risk patients. A decrease of thrombocytes and leucocytes count in peripheral blood, as a result of myelosuppression, is frequently observed and has a nadir of 3-5 weeks. The occurrence of grade 3 or 4 toxicity is dependent on previous (myelosuppressive) therapy and bone marrow disease. Haematological toxicity is usually temporary with complete or partial recover within 6-8 weeks up to the next 3 months. after treatment. The rate of recovery depends on the administered activity and the bone marrow reserve.
Post-therapy scintigraphy, when feasible, might be of value to check tumour extent and radiopharmaceutical distribution and to perform dosimetry calculations.
“Flare” phenomena can occur with increase of pain symptoms, in about 10% of the patients, usually within 72 h, typically transient, usually mild and self-limiting and usually responding to standard analgesics. Generally, flare phenomena are associated with good clinical response.
When cervicodorsal spinal metastases are present, an increase rate of spinal cord compression is possible. Prophylactic corticosteroids may be considered according to local protocols.
[186Re]Re-HEDP was used for pain reduction as supportive care for symptomatic bone metastases from prostate cancer and other (osteoblastic) malignancies in a few European Countries. [188Re]Re-HEDP can be used in some European countries for pain reduction as supportive care for symptomatic bone metastases from prostate cancer and other (osteoblastic) malignancies based on a compassionate use program without marketing authorization.