Radium-223 dichloride therapy is indicated to patients with prostate cancer when medical and surgical castration does not work, cancer causes symptoms by spreading to bones, and there is no known organ metastasis.
What is Radium-223 Therapy?
Theranostic is a recently developing field of the medicine. This approach takes body images using a tumor-specific agent to locate the tumor and its metastasis and their potential future locations and it also uses a specific agent with pre-determined therapeutic efficiency for the diseased tissue. This approach enables switching from traditional medicine to contemporary personalized medical procedures.
For prostate cancer, F-18 NaF PET/CT allows visualization of bone metastases with high sensitivity, while specific and targeted therapies of tumor tissues can be carried out with Radium-223. This is a rather successful example oftheranostic procedures.
There are findings of bone metastasis, which is the leading cause of mortality, disability and lower quality of life in 90% of patients with castration resistant metastatic prostate cancer. Contrary to many other types of cancer, majority of deaths in case of prostate cancer are caused by bone metastasis and complications.
How is Radium-223 Used in Treatment?
Radium-223 is a radioactive element that selectively binds to increased bone turnover zones in bone metastases and radiates very short-range and high-energy alpha particles (< 100 μm). Radium-223 dichloride (223RaCl2) molecule binds to recently formed osseous stroma like osteoblastic or sclerotic metastases by mimicking calcium and then, radiation from high-energy alpha particles creates powerful and quite localized cytotoxic effect in metastases by causing double-strand DNA fragmentation. The short-range of alpha particles helps to minimize toxic effects on adjacent healthy tissue and especially bone marrow.
Radium-223 with therapeutic effect based on emission of radioactive alpha particles is the only bone-specific drug with known positive effect on the survival. ALSYMPCA study that included 921 symptomatic mCRPC patients has demonstrated that Radium-223 therapy prolongs the overall survival by 3.6 months. In addition, a delay in the first skeletal-related event, improvement in pain scores and boosted quality of life have also been found to be related to Radium-223 therapy. In addition to all those positive outcomes, Radium-223 related toxicity is also at minimum levels, except for hematologic toxicity and diarrhea.
Use of Radium-223 for cases of prostate cancer which are resistant to medical and surgical castration, have spread to bones and cause symptoms but without any documented organ metastasis was approved by the FDA in May 2013, and by the EMA in November 2013; then, the therapy was added to major guidelines (NCCN, European Neurological Society) for this indication.
Who are the Candidates for Radium-223 Therapy?
Radium-223 dichloride is indicated for adult castration-resistant prostate cancer cases with symptomatic bone metastases and no documented organ metastases that progress in spite of at least two lines of systemic therapy or that are not eligible for current systemic treatments for mCRPC. Combination of Radium-223 therapy with abiraterone acetate and prednisone/prednisolone is contraindicated. However, a combination with monotherapy or LHRH analogues can be used to increase survival and boost the quality of life along with palliation of pain.
Is Radium-223 Therapy Safe?
Alpha particles with very short range (<100 μm) used in Radium-223 therapy minimize myelosuppression and have limited effect on healthy tissue. Therefore, compared to other cytotoxic systemic therapies, Radium-223 is associated with low myelosuppression rates and lesser side-effects.
A combination of Radium-223 therapy with abiraterone acetate and prednisone/prednisolone is contraindicated.
Clinical efficiency and safety of concomitant Radium-223, abiraterone acetate and prednisone/prednisolone therapies have been investigated in the “ERA-223” study – a randomized, double-blind, place-controlled trial on chemotherapy-naïve patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer associated with bone metastases – and preliminary data have demonstrated that incidence of fracture and death is higher in patients receiving Radium-223 therapy combined with abitraterone acetate and prednisone/prednisolone compared to the patients receiving placebo in combination with abitraterone acetate and prednisone/prednisolone. The same study has demonstrated that concomitant use of bisphosphonates or denosumab decreases incidence of fracture in both treatment arms.
Radium-223 therapy should not be given within the first 5 days following the final dose of abiraterone and prednisone/prednisolone. Similarly, systemic anti-cancer treatment should not be started earlier than 30 days after the last dose of Radium-223 therapy.
Long-term cumulative radiation exposure can be associated with the increased risk of cancer. Especially risk of osterosarcoma, myelodysplastic syndrome and leukemia may increase. However, no cancer case caused by Radium-223 has been reported in clinical trials for follow-up periods up to 3 years.
Due to fecal excretion of radium-223 dichloride, radiation can cause exacerbation of acute inflammatory bowel disease. Therefore, the benefit should be carefully weighed against the risk for patients with acute inflammatory bowel disease.
Osteonecrosis of the jaws is a rarely seen, although important, side-effect of bisphosphonates. Therefore, risk of osteonecrosis of the jaw increases in patients for whom bisphosphonates are used in combination with Radium-223.
Preparation before Radium-223 Therapy
Blood count is done before starting Radium-223 therapy and before each cycle due to bone marrow suppression.
Before the first cycle;
Absolute neutrophil count should be ≥1.5 x 109/L
Platelet count should be ≥100 x 109/L
Hemoglobin reading should be ≥10 g/dL
Before subsequent cycles;
Absolute neutrophil count should be ≥1 x 109/L
Platelet count should be ≥50 x 109/L
The next cycle should be stopped if there is no improvement in targeted blood count values in spite of standard care within 6 weeks after the last cycle of Radium-223 dichloride.
As radium-223 is not metabolized in liver and it is not excreted into the hepatobiliary system, it is not expected that hepatic failure would affect pharmacokinetics of Radium-223 dichloride.
As excretion by urine is minimal and the main excretion is via feces, it is not expected that renal failure would affect pharmacokinetics of Radium-223.
Bone status (e.g. bone scan, bone mineral density) and risk of fracture (e.g. osteoporosis, less than 6 bone metastases, use of drug that increases risk of fracture, low body mass index etc.) should be assessed before and during Radium-223 dichloride therapy. Cases should be followed up for at least 24 months. Patients with higher baseline fracture risk should be assessed carefully in terms of benefits against potential risks.
It has been reported that concomitant use of bisphosphonates and denosumab decreases incidence of fracture for patients treated with Radium-223. Therefore, such preventive measures should be taken before starting or maintaining treatment with Radium-223 dichloride.
For patients with spinal compression or bone fracture, standard treatment of these disorders should be performed before Radium-223 therapy.
As Radium-223 is excreted from bowel, treatment requires thorough care for patients with inflammatory bowel diseases (ulcerative colitis, Crohn disease etc.) and high risk of intestinal obstruction. Patients with constipation may also require careful monitoring and additional supportive measures.
How is Radium-223 Therapy Administered?
Standard method: In total 6 cycles at 4-week intervals; the dosage recommended for each cycle is 55 kBq (1.49 μCi) Radium-223 dichloride per kg body weight.
Ready-to-use Radium-223 dichloride solution is infused into a peripheral IV access at the Nuclear Medicine Clinic. Permanent catheters (e.g. Hickman catheter, infusion port etc.) are not used for the injection.
Before Radium-223 is administered, patency of IV access is checked by irrigating it with at least 10 ml of saline. Radium-223 is slowly infused into a vein for 1 minute and then the intravenous access is irrigated again with at least 10 ml of saline.
Following the intravenous injection, Radium-223 dichloride is rapidly cleansed from the blood and its uptake will first occur in bones and bone metastases, and it is excreted to intestines.
The most common adverse reactions in patients receiving Radium-223 therapy (≥% 10) are nausea, diarrhea, vomiting and peripheral edema. The most common hematologic laboratory anomalies (≥% 10) are anemia, lymphopenia, leucopenia, thrombocytopenia and neutropenia.
- Patients should comply with blood count follow-up appointments and should be informed about signs of bleeding or infection.
- Good hydration should be ensured; oral intake, fluid balance and urine output should be monitored.
- Signs of dehydration, hypovolemia, urinary retention or renal failure should be noted.
- No restrictions are required regarding physical contacts with other people after the therapy.
- Good hygiene practices should be observed during Radium-223 therapy and at least for 1 week following the date of the last dose.
– Patients should use the toilet in sitting position and flush at least twice after each use.
-Clothes of the patient contaminated with feces or urine should be washed immediately and separately from other clothes.
- Caregivers should take universal precautions while handling body fluids, such as use of gloves and apron, and should wash their hands afterwards to prevent contamination.
- Patients with active sex life should use condoms and their female partners with conception potential should use an effective contraception method during the treatment and for 6 months after it is completed.