Radium-223 (Alpharadin)

An alpha particle emitting radiopharmaceutical used to treat metastatic castrate resistant prostate cancer.

Ra-223 is a calcium mimetic that forms complexes with hydroxyapatite in areas of increased bone turnover, as in osseous metastases.

Ta-223 emits particle radiation, which has a short path length and results in high energy transfer.

These properties are responsible for its localized antitumor effect which is mediated by double strand DNA breaks.

Ra-223 has a half-life of 11.4 days and emits 4 alpha particles of varying energy and detectable gamma radiation.

It is excreted mainly through the intestine.

Approved for hormonally refractory prostate cancer and symptomatic bone metastases and no known visceral metastatic disease.

Men with bone metastasis and lymph node metastasis can benefit from radiation-223 therapy.

Extremely well-tolerated agent.

Not indicated for patients with known metastatic visceral disease.

Used in patients with bone predominant disease who were pretreated with chemotherapy or unfit for chemotherapy.

When used in patients refractory to previous therapy associated with a median survival of 14.9 months vs 11.3 months for placebo.

Only appropriate treatment with no visceral metastases and with lymph nodes less than 3 cm. in size.

Thrombocytopenia may occur, rarely, the end of a six-month course of treatment.

Recovery from thrombocytopenia is slow.

Treatment is generally 6 cycles admiistered once every 4 weeks.

PSA is not a useful measurement of response as it typically rises during treatment.

If PSA has declined usually does so after 4-5 months of treatment.

Alkaline phosphatase levels almost always decrease during treatment but does not measure response.

In a multicenter, randomized study of patients with metastatic castration resistant prostate cancer with symptomatic bone metastases demonstrated in patients who received radium-223 lived 30% longer than those who received a placebo (Alpharadin in Symptomatic Prostate Cancer investigating Alpharadin).

Clinical benefit from 223Ra occurred regardless of prior docetaxel use and produced significant improvement in patient quality of life and fewer hospitalizations than placebo, and was larger with concomitant use of bisphosphonates. 

In the above trial patients who received prior docetaxel had a median overall survival of 14.4 months in the radium-223 arm versus 11.3 months in the placebo arm, while in patients who have not received previous docetaxel the median overall survival was 16.1 months in the radium-2-3 arm and 11.5 months in the placebo arM.

In a phase 3 study of patients with symptomatic bone metastases castrate resistant prostate cancer extended survival rates a median of 3.6 months for a trial population inclusive for both pre-and post docetaxel patients.

In a study of the addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event free survival in patients with castration resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo (Smith M).

For men with asymptomatic or mildly symptomatic mCRPC, using bone-protecting agents during treatment with radium-223 plus enzalutamide controlled the risk for fractures.In the randomized phase 3 EORTC-1333-GUCG/Peace-3 trial investigators randomized patients 1:1 to receive either enzalutamide at 160 mg daily plus radium-223 at 55 kBq/kg every 4 weeks for 6 cycles, or enzalutamide alone.

Radiographic progression-free survival served as the primary end point.

It was made mandatory to use a bone-protecting agent in all patients for at least 6 weeks before starting radium-223. 

Before administering the safety letter, 45.2% of patients had not received a BPA, compared with just 3% who had not after the letter was sent out.

The cumulative incidence of fractures at 1 year was 37.1%, in the combination arm and 15.6% in the enzalutamide alone arm. 

In men who received a BPA, the 1-year incidence of fractures was reduced to 2.7% and 2.6%, respectively.

At 18 months, the cumulative incidence was 45.9% in the combination arm and 21.9% in the enzalutamide alone arm, without a BPA. 

With a BPA, the incidence was 4.3% and 2.6%, respectively.

Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated an overall survival benefit in men with mCRPC.

In the randomized, double-blind, placebo-controlled ERA223 trial, investigators evaluated the use of concurrent treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium-223 (55 kBq/kg) in 806 patients with mCRPC: BPAs significantly reduced the rate of fractures in both treatment arms.

Treatment with androgen-deprivation therapy (ADT)] can induce bone loss. 

Bone protecting agents can also delay the time to a first skeletal-related event [SRE] in men with castration-resistant prostate cancer and bone metastasis.

Delays onset of pain and also preserves health-related quality-of-life.

A small percentage of patients have grade 3-4 anemia, thrombocytopenia, and neutropenia.

Blood counts should be obtained prior to treatment initiation and before every dose in patients receiving this drug, and those with compromised bone marrow reserve should be closely monitored.

Myelosuppression and diarrhea were the most frequent adverse events associated with 223Ra.

Its most common adverse effects with G.I. disturbances and bone pain.

Grades three and four hematologic toxicity was detected rarely.

Chemotherapy naïve patients are significantly more likely to complete the full course of treatment.

Better outcomes for Ra-223 3 therapy for patients treated earlier in the disease process.

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