European Nuclear Medicine Guide
Radiopharmaceutical: [223Ra]RaCl2, [223Ra]Radium-Chloride, radium-223 dichloride (Xofigo®, formerly Alpharadin®)
Nuclide: Radium-223; four high energy, 5.6-74 MeV, short range, <100 μm, α particle emissions.
Activity: 55 kBq/kg body weight administered with a 4-week interval .[70]
Administration: Radium-223 is administered by intravenous i.v. injections, once a month for six months.
A dedicated EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer has been published [47].
Radium-223 is an alpha emitter with a half-life of 11.4 days which decays to stable lead (Pb) via a chain of five daughters, but most, ~95%, of the energy is emitted as alpha radiation. Since the third daughter, 211Pb, has a half-life of 36 minutes, there is a possibility that subsequent disintegrations could occur elsewhere, but no redistribution of radioactive daughters has yet been reported.
Radium-223, a Group 2 metal, shares similar chemical properties with calcium. As such, divalent cationic [223Ra]Ra2+ has high avidity to newly deposited osteoid, especially within the microenvironment of osteoblastic or sclerotic metastases. There, the high- energy alpha-particle radiation induces mainly double-stranded DNA breaks that result in a potent and highly localized cytotoxic effect. The short path of the alpha particles also means that toxic effects on adjacent healthy tissue, and particularly the bone marrow, are minimized.
Following intravenous injection, [223Ra]RaCl2 is rapidly cleared from the blood and is incorporated primarily into bone and bone metastases or excreted into the intestine. Fifteen minutes post injection, about 20% of the injected activity remains in the blood. At 4 h, about 4% of the injected activity remains in the blood and continues to decrease to less than 1% at 24 h after the injection. The volume of distribution is higher than the blood volume indicating distribution to peripheral compartments. At 10 min post injection, activity is observed in the bone and in the intestine. The level of activity in the bone is in the range of 44% to 77% at 4 h post injection.
No significant uptake is observed in other organs such as heart, liver, kidneys, urinary bladder, or spleen at 4 h post injection. Faecal excretion is the major route of elimination from the body. About 5% is excreted in the urine, and there is no evidence of hepatobiliary excretion. Whole body measurements taken 7 days after injection (after correcting for decay) indicate that a median of 76% of the administered activity is excreted from the body. The rate of elimination of Radium-223 from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population with the normal range from once daily to once weekly bowel evacuation. This may also be influenced by medications such as morphine derivatives.
According to recent EMA authorisation [223Ra]RaCl2 is indicated in patients that meet the following criteria:
Clinical trials employing [223Ra]RaCl2 in other diseases than prostate cancer have been conducted or are ongoing [71–73].
Absolute:
Xofigo is contraindicated in combination with abiraterone acetate and prednisone/prednisolone
Relative
[223Ra]RaCl2 must be administered by slow, generally up to 1 minute, i.v. injection. The i.v. access line or cannula must be flushed with isotonic saline before injection. Once [223Ra]RaCl2 has been correctly administered, there is minimal external dose rate from the patient. The product can be administered on an out-patient basis, and there are no restrictions on normal interactions with friends or relations.
The low yield of photons combined with the low amount of activity administered makes quantitative imaging of Radium-223 challenging. However, it has been demonstrated that prolonged gamma camera imaging is feasible, and that activity can be quantified to within 20%-50%, depending on the volume imaged [74]. Medium energy general purpose collimators and energy windows centred at 82 keV, and possibly 154 keV and 270 keV, are recommended.
Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, have been reported in patients treated with [223Ra]RaCl2. Therefore, haematological evaluation of patients must be performed at baseline and prior to every administration as well as Alkaline Phosphatase (ALP) and PSA measurement. Treatment may be delayed up to 6 weeks of the last administration of [223Ra]RaCl2 to allow for bone marrow recovery. If this does not occur despite receiving the usual standard of care, further treatment with [223Ra]RaCl2 should only be continued after a careful benefit/risk evaluation. Patients with evidence of compromised bone marrow reserve, e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT), or prostate cancer patients with advanced diffuse infiltration of the bone (“superscan”), should be treated with caution. An increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia was observed in these patients during a phase III study [75].
An assessment of bone health before and during treatment should be performed in each patient to evaluate the risk of fracture and closely monitored for at least 24 months after discontinuation of [223Ra]RaCl2. In patients with a high baseline risk of fracture, carefully consider the benefit of treatment against the risks. Concurrent use of bisphosphonates or denosumab has been found to reduce the incidence of fractures in patients treated with [223Ra]RaCl2 in the ongoing EORTC 1333/PEACE III trial [76].
Any subsequent systemic cancer treatment should not be initiated for at least 30 days after the last administration of [223Ra]RaCl2.
Extensive neurological examination should be a standard part of the analysis for patients with painful skeletal metastases. External radiotherapy (or even neurosurgery) is preferred in patients with myelum compression or neurological deficit.
Skeletal scintigraphy or 18F Fluoride PET/CT should be performed no later than 3 months after completing 6 treatments to evaluate response to treatment. An intermediate evaluation with skeletal scintigraphy and thorax abdomen CT scan after 3 treatments should be also performed in case of suspicion of disease progression. To be noticed that a “flare phenomena” can induce a transient increase of bisphosphonate uptake at scintigraphy.
The recommended activity for [223Ra]RaCl2 is 55 kBq per kg body weight given at 4-week intervals for 6 injections. This absorbed radiation dose calculation was performed based on clinical bio-distribution data. For Radium-223, primarily an alpha emitter, additional assumptions were made for the intestine, red marrow, and bone/osteogenic cells in order to provide the best possible absorbed dose calculations for [223Ra]RaCl2 considering its observed bio-distribution and specific characteristics [70].
To date, a study has investigated absorbed doses to metastases in 9 patients and 24 metastases using gamma camera imaging at different time points (1-5 hours, 18-24 hours, 48-60 hours, 7 and 15 days). The absorbed dose (D) estimated after the first injection was 0.7 Gy (range 0.2-1.9 Gy).
The absorbed dose to normal tissues has been estimated with the ICRP model for Radium-223 [77]. Bone endosteum, red bone marrow, liver, colon and intestines were reported to receive the highest absorbed doses. For normal organ due to physiological uptake the bone endosteum was calculated to receive the highest absorbed doses at 7.5x10-7 Gy Bq-1 for alpha and 1.1x10-8 GyBq-1 for beta/gamma. The absorbed doses to the red marrow were 7.2x10-8 Gy Bq-1 and 5.5x10-9 Gy Bq-1 respectively and with a corresponding cumulative absorbed alpha dose to the red bone marrow of approximately 17 Gy after a series of six treatments for a 70-kg person with an overall administered activity of 23 MBq of [223Ra]RaCl2. In an imaging-based bio-distribution study, [223Ra]RaCl2 was found to rapidly clear from the blood, and the main route of excretion was found to be via the small bowel [78].
A study of normal tissue dosimetry which included 6 patients treated twice with 100 kBq/kg of [223Ra]RaCl2 showed that absorbed doses delivered to normal organs vary by an order of magnitude as assessed by sequential quantitative imaging, external counting, and urine and faecal collection [79]. Absorbed doses from a single administration of 50 kBq/kg were 2.3-13.1 Gy/MBq for bone surfaces, 14-66 mGy/MBq for whole body, and 0.2-1.9 Gy for red marrow.
The ALSYMPCA phase Ill study of patients with progressive castration-resistant metastatic prostate cancer showed that median overall survival was longer among patients who received [223Ra]RaCl2, 14.9 months (95% Confidence Interval (CI) 13.9-16.1), was longer than patients who received placebo, 11.2 months (95%CI 9.0-13.2; Hazard ratio 0.695 95%CI 0.581-0.832) [75,80]. In addition, the time to first symptomatic skeletal event, and the time to increases in alkaline phosphatase and prostate-specific antigen levels were prolonged. Reduction in pain was not an endpoint of the registration studies.
A sub analysis of the ALSYMPCA trial showed that [223Ra]RaCl2 is also effective and well tolerated irrespective of previous docetaxel use [75].
The efficacy and safety of cytotoxic chemotherapy performed after treatment with [223Ra]RaCl2 has not been established. The limited data available indicates that patients who receive chemotherapy after [223Ra]RaCl2 have a similar haematological profile as patients who receive chemotherapy after placebo.
A Phase I/IIa study evaluated the association of docetaxel and [223Ra]RaCl2. Twenty patients were included in phase 1 dose escalating study and 53 patients in phase IIa study (36 to combination treatment and 17 to docetaxel alone). The exploratory results show that the combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers but comparative studies with clinical benefit end-point are not available [81].
Furthermore, a randomized phase II trial of three dosing regimens ( standard protocol vs 88 kBq/kg q4w for six cycles vs 55 kBq/kg q4w for 12 cycles ) including 391 patients demonstrated that high-dose or extended regimens do not result in changes in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs [82].
There is no evidence as yet of correlations between the absorbed doses delivered and effect.
Grade 1 and 2 injection site reactions, such as erythema, pain and swelling, were reported in 1.2% of patients, thrombocytopenia (all grades) occurred in 11.5% of patients, grade 3 and 4 thrombocytopenia were observed in approximately 6.5% of patients, neutropenia (all grades) was reported in 5% of patients, grade 3 and 4 neutropenia was observed in 2.2% of patients, and neutrophil and platelet count nadirs occurred mostly at 2-3 weeks after intravenous administration of a single dose of [223Ra]RaCl2 [83]. The short range of the alpha particles (<100µm) emitted from [223Ra]RaCl2 distributed on trabecular bone surfaces probably contributes to a heterogeneous dose profile in the marrow space, and this could explain the observed low haematological toxicity.
Most commons Adverse reactions to Radium-223 are presented in Table 1.
Table 1. Adverse Reactions to [223Ra]Radium-ChlorideRaCl2
|
|
Very common (≥1/10) |
Common (≥1/100 to |
Uncommon (≥1/1,000 to |
|
Blood and lymphatic |
Thrombocytopenia |
Neutropenia, Pancytopenia, Leukopenia |
Lymphopenia |
|
Gastrointestinal |
|
Diarrhoea, Vomiting, |
|
|
Administration Site |
|
Injection Site Reactions |
|
In the phase I/IIa trial from Morris et al comparing docetaxel alone vs the association of docetaxel and [223Ra]RaCl2, the former was well tolerated and the safety profile of the two treatment groups was similar except for higher rate of febrile neutropenia in the docetaxel monotherapy arm (15% vs 0%) [81].
On the other hand, a blind phase III randomized trial (ERA-223 study) including 806 patients treated with abiraterone in association to [223Ra]RaCl2 or abiraterone in association to placebo was unblinded prematurely because of more fractures and deaths reported in the [223Ra]RaCl2 group compared to placebo group. Fractures (any grade) occurred in 29% of 392 patients in the [223Ra]RaCl2 group vs 11% of 394 patients in the placebo group [84].
The difference in survival was no longer statistically significant after correction for baseline imbalances between groups (HR 1.06; 95% CI 0.84 – 1.25; P=0.605) [85].
At this moment [223Ra]RaCl2 is recommended to be used as monotherapy, in particular the use of [223Ra]RaCl2 in combination with, or within 5 days of discontinuation of abiraterone acetate and prednisone/prednisolone is not recommended.
In May 2014, the European Commission approved the marketing authorization of [223Ra]RaCl2 (Xofigo®) for the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Approval of [223Ra]RaCl2 was based on ALSYMPCA phase III trial results demonstrating an improved survival in patients who received treatment and pain was not an endpoint in the registration studies. In July 2018 the European Medicine Agency (EMA) restricted its use to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments. Furthermore, [223Ra]RaCl2 must also not be used with the medicine abiraterone acetate (Zytiga) and prednisone/prednisolone, and should also not be used with other systemic cancer therapies, except in combination with an LHRH analogue to suppress male hormones (EMA / 680161 / 2018).
[223Ra]RaCl2 is not indicated for patient with bone metastases from other cancers than prostate cancer except for clinical trials.