By William K. Oh, MD + Charlie Baker
The Tisch Cancer Institute | Icahn School of Medicine at Mount Sinai
Radium-223 is used to treat bone metastases, a common problem for men living with metastatic hormone resistant prostate cancer (MHRPC), affecting up to 90% of these patients. When the disease progresses, it can be painful and difficult to treat. Given these potentially debilitating problems, we are constantly looking for new ways to improve our current treatment regimen. The development of a drug called radium-223 (brand name: Xofigo) is a substantial innovation, not only because it causes less toxicity compared to its predecessors, but also because it prolongs life. Patients can now access an agent that treats bone metastases and will improve both quality and duration of life.
What is Radium-223 and how does it work?
Radium-223 harnesses the physical properties of radium, a radioactive element with similar molecular properties to calcium. Just as calcium is incorporated into bone, so too can radium be incorporated. Because bone metastases induce and activate newly-synthesizing bone, radium is incorporated preferentially into the sites of active metastases. Once radium has accumulated at these sites, it emits radioactivity that damages the surrounding cancer cells. Some of the readers may know the history of radium’s harmful effects from the famous “Radium Girl” lawsuits in the early 1900’s, which involved the negative health outcomes of employees using radium-containing self-luminous paint for items such as watch hands and instrument switches. While the radium used in that paint was excessively harmful, the type of radium used in Xofigo is actually different. The active component of Xofigo is an isotope of the element radium, meaning that it has a different number of subatomic particles called “neutrons” than other types of radium. This specific number of neutrons gives radium-223 a distinct profile of radioactivity. Unlike other isotopes of radium, like the poisonous kind that hurt watchmakers in the early 20th century, radium-223 gives off a very particular type of radiation that makes it safer for medical use. Of the three main types of radiation —alpha, beta, and gamma—radium-223 primarily emits alpha radiation (also called “alpha particles”). Alpha radiation, distinct from beta and gamma radiation, is powerful yet relatively safe—powerful for its distinctive high linear energy and safe for its characteristic short distance of travel. The high energy alpha particles cut through the DNA of the cancer cells but do not travel very far beyond them, with an average trajectory of only 100 micrometers (about ten cells in diameter). Because radium-223 is incorporated mainly at sites of bone metastasis, this cell-killing alpha radiation is targeted predominantly at the cancer cells, keeping your native healthy bone tissues fairly safe.
Radium-223 is given by specialized doctors trained in either nuclear medicine or radiation oncology. Xofigo is injected monthly for a total of 6 months. Not every hospital or office offers it, but referral centers are available for most patients in the US.
How does radium-223 affect prostate cancer?
Radium-223 was approved by the FDA in 2013 after the randomized ALSYMPCA trial demonstrated numerous advantages over placebo. These advantages included delayed symptomatic skeletal events, reduced levels of biochemical indicators of disease (such as PSA and alkaline phosphatase blood levels), and—most importantly—a significant increase in survival.
Symptomatic skeletal events (or SSEs) are a painful consequence of uncontrolled bone metastases. The ALSYMPCA trial scrutinized the time it took for SSEs to occur. This time was defined as the interval between the administration of radium-223 (or placebo) and the occurrence of SSEs such as bone fracture, spinal cord compression, or the necessity of surgery or external beam radiation therapy to treat symptoms. For the patients who received radium-223, the median time to one of these events was extended by 5.8 months compared to placebo. This notable advantage can provide our patients with a significant quality of life benefits.
The trial also analyzed the effect of radium-223 on both alkaline phosphatase (ALP) and prostate specific antigen (PSA) levels. Abnormal bone tissue development, such as that seen in bone metastasis, can increase ALP levels, making ALP a blood-based indicator of potentially active bone metastases. Radium-223 often reduced ALP levels, with a significantly larger proportion of radium-223 patients experiencing at least a 30% reduction compared to the placebo group.
Radium-223 may also reduce PSA levels. As most know, PSA levels are an indicator of cancer progression, with higher PSA values corresponding to worse outcomes. A significantly larger proportion of the radium-223 patients experienced at least a 30% reduction in PSA levels compared to the men who received a placebo. Although most patients do not experience a decline in PSA, they may notice a slowing of the PSA rise, which is a more common outcome with radium-223.
The most significant benefit of radium-223 is its proven survival benefit compared with the placebo group, reducing the relative risk of death by 30%. Indeed, the ALSYMPCA study reports that radium-223 can increase median survival time by 3.6 months, even in a group of men with very advanced prostate cancer. As a reminder, this is a median difference, which means that some patients might have benefited much more, and others less.
Of note, in the ALSYMPCA trial patients were allowed to receive radium-223 alone, or in conjunction with the best standard of care, which could include external beam radiation therapy (EBRT), corticosteroids, antiandrogens, estrogens, estramustine, ketoconazole, and various emerging hormonal therapies. Thus, the results of the ALSYMPCA trial demonstrate what you might expect to see if radium-223 is added to other effective anticancer therapies administered at the same time. Considering the present state-of-the-art, this may include newer androgen-targeted drugs like abiraterone acetate (Zytiga) and enzalutamide (Xtandi).
The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial enrolled 921 patients with metastatic, castration-resistant prostate cancer. Men in the trial were randomly assigned to receive either radium-223 (six intravenous injections, one every 4 weeks) plus the best standard of care or a placebo plus the best standard of care. The trial’s primary endpoint was overall survival. Secondary endpoints included time to the first symptomatic skeletal event—such as a bone fracture, spinal cord compression, or the need for radiation to treat bone-related symptoms—and quality-of-life measures. The trial was funded by Bayer Healthcare Pharmaceuticals and Algeta, the company that developed and manufactures radium-223. Source: http://www.cancer.gov/
What are the side effects of Radium-223?
Because of its closely targeted delivery and highly localized activity, radium-223 has relatively few side effects. The most common are diarrhea, nausea, vomiting, and thrombocytopenia (low platelet count). Diarrhea occurred in about 25% of the radium group and 15% of placebo patients.
The most serious side effects relate to a potential effect on blood counts. Thrombocytopenia occurred in 11.5% of patients on radium-223 and 5.6% of patients on placebo, while neutropenia (a low white blood cell count) occurred in 6.3% of patients on radium-223 and 2% of patients on placebo. Anemia (a low red blood cell count) may also worsen on radium-223, though mild to moderate anemia is already common in many men with advanced prostate cancer.
Since there is a risk that Xofigo may lower blood counts, patients must have adequate blood counts (white and red cells, as well as platelets) before the first injection. With each subsequent treatment, their blood counts (particularly the white count and platelets) must remain above a certain cutoff to allow continuation of the monthly therapy.
Who is eligible to take Radium-223?
Xofigo is intended to treat symptomatic bone metastases in patients whose prostate cancer is hormone-resistant, meaning the patient’s PSA levels do not respond to Lupron. To be eligible, the patient should not have any cancer in the “soft tissues” such as the liver or lung. Small amounts of metastatic disease in the lymph nodes is permissible, however, because limited disease in the nodes is nowhere near as dangerous as bone disease. The reason Xofigo is withheld from men with liver or lung metastases is that radium-223 attacks only the bone metastases; so it would not be expected to have any effect on cancer that is located in the liver or lung.
Given the risk of bone marrow suppression, it is not recommended that chemotherapy (such as docetaxel or cabazitaxel) be administered concurrently with Xofigo, although clinical trials of the combination are currently underway. Prior chemotherapy does not preclude patients from receiving radium-223. In fact, the ALSYMPCA trial stratified its participants by their status and found that radium-223 has similar efficacy in patients who have, or have not received previous chemotherapy. Even people who were considered too frail to be treated with docetaxel were allowed to receive Xofigo. This means that although efficacy is demonstrated to be similar for pre- and post- chemotherapy patients, studies to determine the optimum sequencing of radium-223 are currently underway.
Given radium-223’s relatively low toxicity and excellent safety profile, it fits nicely into the evolving standard of care for patients with hormone-resistant prostate cancer. Newer treatments such as cabazitaxel, abiraterone, and enzalutamide do not overlap mechanistically with radium-223, so all these agents may be used in sequence and help patients via different approaches.
Xofigo represents an important new treatment option for men with bone metastases and hormone resistance. It improves both quality of life and overall survival. In that regard, radium-223 can make a big difference to patients and their families living with advanced prostate cancer.