More than 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases which leads to a significant increase in morbidity and mortality.1,2 Patients with metastatic prostate cancer and bone involvement have only a 3% five-year survival, whereas the five-year survival of patients without bone metastases is 56%. Skeletal-related events (SRE) in mCRPC patients may cause potentially devastating effects, such as decreased survival and pain, impaired mobility and spinal cord compression.2 Bone metastases and SREs diminish a patient’s quality of life and increase medical costs.3,4
Radium-223 dichloride (radium-223), a radiopharmaceutical which is injected intravenously, is the first and only targeted α-particle emitter approved by the FDA in the United States for treatment of bone metastases from prostate cancer.
Radium-223 resides in the same group of elements in the periodic table as calcium, thus it acts as a bone seeking calcium mimetic and selectively binds to areas of increased bone turnover which is seen with bone metastases. Non target localization in soft tissues is limited. As a targeted alpha particle, radium-223 predominantly emits alpha particles as opposed to beta emitters such as ytrrium-90 and strontium-90. Alpha particles have a short range of radioactive emission thereby minimizing toxic effects on adjacent healthy tissue. Beta particles have a much longer range which results in greater damage to normal cells. Beta particles deliver a few hundred keV of energy over a few millimeters, alpha particles deliver a bigger punch of 5 MeV, over a much shorter distance on the order of a few microns. That very large amount of energy deposited in short range makes them more cytotoxic to the cell than beta emitters generating highly localized and intense radiation zones that induce nonrepairable, doublestranded DNA breaks. The highly targeted nature of radium-223 helps preserve the surrounding healthy bone marrow, thereby limiting side effects. The use of radium-223 has been reported to improve overall survival (OS) rates, and extend the time to first symptomatic SRE in men with mCRPC and symptomatica osseous metastases. Improving OS rates and reducing the risk for symptomatic skeletal-related events are critical in the treatment of mCRPC patients.5
Alpharadin (radium 223) in Symptomatic Prostate Cancer Patients (ALSYMPCA) was the pivotal phase III clinical trial that led to the US Food and Drug Administration (FDA) approval of radium-223 for the treatment of patients with mCRPC, symptomatic bone metastases and no known visceral metastatic disease. The ALSYMPCA trial enrolled 921 patients with symptomatic CRPC and skeletal metastases who were not eligible for, or declined treatment with docetaxel. Patients were randomly assigned in a two to one ratio to six monthly injections of radium-223 or a matching placebo. Patients also received the best standard of care for their disease and symptoms, including external beam radiation therapy (EBRT) and/or abiraterone therapy. At the interim analysis ALSYMPCA demonstrated OS rates in the radium-223 group significantly improved compared to placebo (14 months vs. 11.2 months). Consequently the trial was halted early for efficacy. The final updated analysis confirmed the radium-223 survival benefit with an OS rate of 14.9 months in the radium-223 arm compared to 11.3 months in the placebo arm, (P<0.001).5
The ALSYMPCA trial also demonstrated benefit on symptomatic SREs in men with bony mCRPC. Symptomatic SREs occurred in 202 (33%) of the 614 patients in the radium-223 group compared to 116 (38%) of the 307 patients in the placebo group. Time to first symptomatic SRE was prolonged in the radium-223 group with a median of 15.6 months compared to 9.8 months with placebo treatment, (P=0.00037). The trial also revealed that radium-223 reduced the risk of pain and spinal cord compression morbidities compared with placebo (HR=.67). Radium-223 did not significantly increase the risk for pathologic bone fractures or tumor-related orthopedic surgical interventions.6
In the ALSYMPCA trial, 12 percent of patients in the radium-223 group suffered thrombocytopenia, compared with 6 percent in the placebo group, and 5 percent of patients who received radium-223 had neutropenia compared with 1 percent of patients who received placebo.5 The overall safety profile with radium-223 (targeted alpha-particle) is very good, especially when compared to other standard bone-seeking beta-emitters. This safety profile is likely a direct result of the fact that radium-223 has a short range of activity thereby limiting the amount of non-target radiation.
Importantly, before patients receive radium-223, it is critical to obtain bloodwork prior to undergoing treatment. Prior to the first administration, patients’ Hgb should be greater than or equal to 10 g/dl, the absolute neutrophil count (ANC) should be 1.5 X 109/L or higher, and platelet count should be 100 X 109/L or higher. For subsequent doses, the recommended ANC count should be 1 X 109/L or higher, and platelet count must be 50 X 109/L or higher. No minimum Hgb level is included in the package insert for subsequent doses. To safeguard patients, radium-223 should be discontinued if hematological values do not recover within 6 to 8 weeks of the last administration despite supportive care.
Data accumulated since the ALSYMPCA trial indicate that patients who complete at least five cycles of radium-223 achieve the best OS benefit compared to patients who complete just one to four doses. Patients who are least likely to complete the treatment are those with more advanced disease and/or have undergone prior treatments with other therapies. Patients who do not complete all six cycles usually drop out due to disease progression, decreased blood count, or other complications. Unfortunately, patients with symptomatic mCRPC are often not referred for radium-223 therapy until they are diagnosed with late-stage metastatic disease. At that point, there is a lower likelihood that they will complete all six cycles of radium-223 therapy.7
To provide the benefits of radium-223 treatment earlier to patients with mCRPC, we need to better define symptomatology related to bony metastases. Symptoms can manifest in many ways such as fatigue, sleep disturbances, increased distress and irritability, impaired mobility, and difficulty in performing activities of daily living. Today, we often define symptomatic bony mCRPC simplistically as a disease in which patients show signs of bone pain. However, if we wait until patients have painful symptoms to administer radium-223, we may be providing this therapy too late in the disease to result in a survival benefit. Radium-223 treatment earlier may help patients achieve an improved OS from the drug.8-10
We also know from clinical studies that patients with lower alkaline phosphatase (ALP) levels do better with radium-223 treatment. A retrospective review published in 2016 of 110 patients with mCRPC treated at MD Anderson Cancer Center study found that treatment with the radiopharmaceutical produced a significant reduction in ALP and pain, and concomitant abiraterone together with an increased number of radium cycles were associated with improved OS and progression free survival (PFS). The same review also reported that the total number of radium cycles and concomitant EBRT were predictive of bone marrow failure (BMF), but concominant hormonal therapy and chemotherapy treatment were not associated with BMF.11 Further prospective studies are necessary before we should consider the use of radium 223 concurrently with chemotherapy.
Assessing progression and outcomes on radium-223 is more than monitoring prostate specific antigen (PSA) levels. Patients on radium-223 who respond to the radiopharmaceutical can experience an initial symptomatic flare, including a rise in PSA. Signs of progression on radium-223 are often multifactorial, and clinicians should be aware of this when monitoring patients.12 Should we include some comments about alk phos here?
How do we sequence the variety of treatments that improve survival rates of patients with mCRPC? To truly provide patients with the full benefits of current mCRPC therapies, it may be useful to consider changing our perspective to this topic to a layering approach rather than sequencing approach. Compelling data on this topic is not available, but it might be wise to consider more combination therapies especially when there are different mechanisms of action. Clinical trials are investigating some of these combinations using immunotherapy, novel hormonal agents, and radium 223.13 In the past, use of radiopharmaceuticals resulted in serious bone marrow suppression that made it more difficult to administer chemotherapy afterward. However, the ALSYMPCA trial demonstrated that radium-223 can safely be given to patients pre- and post-docetaxel treatment, indicating that radium-223 does not hinder the ability to administer chemotherapy afterwards. This is promising as it also opens the door for more options in the future such as retreatment with radium-223 in select patient groups.
How can a healthcare provider make decisions about whether a second therapy can be added to radium-223 treatment? Studies are investigating whether combining radium-223 with enzalutamide or abiraterone is safe and effective. A prospective trial is now testing outcomes with abiraterone combined with radium-223 in patients with mCRPC, and the results should be available within the next 12 to 18 months.14
At this time concurrent administration of chemotherapy and radium-223 treatment is not recommended. Nevertheless, studies are exploring this possibility, although two treatments that act on bone marrow likely carry an increased risk for bone marrow toxicity. Preliminary data from ongoing studies indicate that lower dose docetaxel combined with radium-223 may be safe. The question of how to sequence prostate cancer drugs in combination with radium-223 is included in the recommendations by the recently published RADAR 2 working group. The RADAR II paper states that following a second-generation androgen pathway inhibitor, radium-223 should be considered for patients with bone metastases upon the emergence of signs and symptoms (ie, fatigue, impaired mobility, previous or current bone pain). The risk of bone metastatic disease can be independently predicted by alkaline phosphatase (ALP) and PSA. And finally The Working Group advises that consideration be given to adding (therapeutic layering) radium-223 to androgen pathway inhibitors in patients with bone metastases and symptoms.15 We expect to see more data that looks at outcomes from retreatment with radium-223 in mCRPC in the next few years. If we can treat our patients with bone metastases earlier in the course of their disease, we may also create a window to retreat them later when they have a higher burden of osseous metastatic disease.
Patients with bone metastases are usually assessed for disease progression by one of several imaging methods each with advantages and shortcomings.16 The timing of imaging scans to monitor the patient’s response to treatment between cycles may not be helpful, because patients on radium-223 may develop more bone metastases during therapy, or may have a flare response, or the changes are undetectable by the imaging method used. In most cases, these responses on bone scan should not serve as an indication to discontinue therapy because the goal is to have patients complete the six cycle of treatment. Another concern for patients undergoing radium-223 therapy is development of visceral metastases during the 5 months of therapy. CT scans should be performed when there is a suspicion of visceral metastases, signaled by increased symptomatology, rapid rise in PSA level, or clinical deterioration.16
Fluoride PET/CT scans have greater sensitivity, specificity, and accuracy than conventional bone scans. 17 18F-fluoride positron emission tomography/computed tomography (PET/CT) bone imaging is possibly a useful tool to predict prognosis and outcomes in patients who receive the radium-223. A 2015 published study of 18F-fluoride PET/CT to assess skeletal metastases, survival rate, and risk of skeletal-related events in patients with advanced bony CRPC who received radium-223 revealed that whole-body skeletal tumor burden was an independent predictor of OS rates and SREs in patients with advanced CRPC who received radium-223.17 In this study, 76 patients were treated with radium-223, and of these, 42 patients had baseline fluoride PET/CT, and the other 31 were assessed with bone scintigraphy and/or conventional bone scans. The study results showed that 57.9% of patients completed all six doses, and OS rates were highly correlated with the number of radium-223 doses. The risk of death decreased by 60% for each subsequent increase in the radium-223 dose, and patients who received all six doses had a 65% reduction in progression-free survival. OS was strongly predicted (R = 0.95;P < 0.0001) by skeletal tumor burden indices (total volume of fluoride avid bone metastases (FTV10) and total fluoride skeletal metastatic lesion uptake (TLF10)). TLF10 was a strong independent predictor of OS, and at a cutoff value of 8,000 discriminated survivors from non-survivors. Bone scintigraphy or bone scans did not predict OS rates.17 Based on these results fluoride PET/CT might be useful for predicting outcomes with radium-223 and for guiding treatment strategies.
Improvement in quality of life was documented in the ALSYMPCA trial. Patients who received radium-223 experienced improvements in insomnia, poor appetite, and pain. Patients on radium-223 may also feel better, and can perform activities they could not prior to receiving the radiopharmaceutical. Even if there is no change in quality of life, radium-223 should be continued, since the goal is OS benefit. 5
Necessary safety precautions should be adhered to when using radium-223 to ensure safety with its handling and administration. Only licensed healthcare providers, such as nuclear medicine physicians or radiation oncologists, are allowed to administer the drug in a designated facility where the providers are comfortable dealing with unsealed sources of radiation and observe protocols for administering radiation. Overall, radium-223 is a very safe drug, and no thick shielding is necessary as a protection against radiation exposure. However, ingestion or inhalation can result in radiation exposure, and therfore, precautions such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination are recommended.
A wide range of healthcare providers—including urologists, oncologists, nurses, nuclear medicine specialists, radiation oncologists and palliative care and pain specialists—need to work together to manage prostate cancer with bone metastases. By taking an individualized multidisciplinary approach to treating mCRPC with radium-223, we can significantly improve survival and quality of life for our patients.
Written By: Phillip J. Koo, MD, Division Chief, Diagnostic Imaging, Banner MD Anderson Cancer Center, Phoenix, Arizona
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