Prostate cancer is the third leading cause of cancer-related death and most common noncutaneous malignancy diagnosed in American men.1 A minority of men have metastatic disease at the time of diagnosis, whereas other men progress from localized or locally advanced disease to develop metastatic prostate cancer.2 Prostate cancer has a propensity to metastasize to bone, with rates of skeletal metastasis as high as 90%.3,4 Patterns and site of metastatic spread have important prognostic implications, and patients with metastatic bone disease can benefit from treatment aimed to the bone.4,5 Initial treatment of metastatic prostate cancer consists of androgen deprivation therapy, and in select cases, chemotherapy with the addition of newer agents once castrate-resistant disease develops. Because metastatic castrate-resistant prostate cancer (CRPC) is incurable,6 the principal goal of treatment is to extend survival and prevent symptomatic skeletal events.7,8
The phase 3 Alpharadin In Symptomatic Prostate Cancer (ALSYMPCA) study examined whether radium Ra 223 dichloride (radium-223) could extend overall survival (OS) in men with CRPC, two or more symptomatic bone metastases, no known visceral metastases, and lymphadenopathy, if present, of ≤3 cm. Eligible patients had received docetaxel or were unfit for docetaxel, which was defined as patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable. Patients were required to have symptomatic disease, which was defined as regular use of analgesic medication or treatment with external beam radiation therapy (EBRT) required for cancer‐related bone pain within the previous 12 weeks. Analysis examined patients receiving radium-223 plus best standard of care (BSOC) against those receiving placebo plus BSOC. BSOC was defined as antihormonal agents, local EBRT, ketoconazole, and treatment with glucocorticoids. The primary endpoint of OS was defined as time from randomization to date of death, regardless of cause.4
Results from the interim analysis, including 809 patients and performed after 314 deaths, demonstrated median OS improvement in those who had received radium-223 compared with placebo 14.0 versus 11.2 months respectively (hazard ratio [HR] 0.695, 95% CI, 0.552-0.875; P = .00185). Radium-223 was associated with a 30% reduction in the risk of death (HR 0.70, 95% CI, 0.55-0.88; P = .002). With these findings, the independent data and safety monitoring committee recommended termination of the trial. An updated analysis confirmed the 30% reduction in the risk of death in the radium-223 arm (HR 0.70, 95% CI, 0-58-0.83; P < .001). In an updated analysis, after 528 deaths, median OS in the radium-223 arm improved to 14.9 months compared with 11.3 months in the placebo-treated group (HR 0.70, 95% CI, 0.58-0.83; P < .001).4
In addition to increases in OS, secondary endpoint results supported the use of radium-223 over placebo. Radium-223 increased the time to first symptomatic skeletal event, defined as the first use of EBRT to relieve skeletal symptoms, new symptomatic pathologic vertebral or nonvertebral bone fractures, spinal cord compression, or tumor-related orthopedic surgical intervention, with median time to first event of 15.6 months versus 9.8 months (HR 0.66, 95% CI, 0.52-0.83; P < .001). The median time to an increase in total alkaline phosphatase level (HR 0.17, 95% CI, 0.13-0.22; P < .001) and time to an increase in prostate-specific antigen (PSA) level (HR 0.64, 95% CI, 0.54-0.77; P < .001) also favored radium-223.4
Radium-223 mimics calcium and forms complexes within bone mineral at areas of increased bone turnover, such as bone metastases from prostate cancer. Radium-223 emits α particles over α distance of <100 μm and induces mainly double-strand DNA breaks, and the short range of radiation limits damage to surrounding normal tissue.9 Radium-223 has a well-documented safety profile but can be absorbed by organs other than bone, primarily the bone marrow and gastrointestinal system, which can result in side effects in healthy tissues.9 The most common adverse reactions seen in subjects receiving radium-223 or placebo in the phase 3 clinical trial included pancytopenia (2% of radium-223–treated patients and 0% of placebo-treated patients, respectively) nausea (36% and 35% of patients, respectively), diarrhea (25% and 15%, respectively), vomiting (19% and 14%, respectively), peripheral edema (13% and 10%, respectively), and renal failure and impairment (3% and 1%, respectively). The most common hematologic laboratory abnormalities among patients in the radium-223 arm (≥ 10%) versus the placebo arm (all Grades [%]), respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%).4,9 In the ALSYMPCA trial, the proportion of men with Grade 3–4 adverse events was lower among patients receiving radium-223 than among patients receiving placebo. The overall incidence of Grade 3–4 events was 57% among radium-223–treated patients and 63% among those receiving placebo.4
Although many agents have been introduced into the metastatic CRPC treatment armamentarium in recent years, questions remain regarding the optimal sequencing of agents.10 Radium-223 is indicated for men with symptomatic metastatic CRPC, with bone metastases, and no known visceral metastases, but is not recommended for use in combination with chemotherapy.4
To incorporate advanced therapeutics into our practice, including radium-223, we adopted a champion model to aid in organization and quality. The four champions model is designed to ensure that the entire practice is focused on improving coordination of patient care, pursuing timely therapeutic interventions, and enhancing practice performance.11 The four champions are the following:
Incorporation of radium-223 occurs along a spectrum that can be divided into three phases:
A practice can choose to offer radium-223 for one or more reasons, including a desire to provide patients with greater in-practice continuity of care, interest in developing an advanced prostate cancer (APC) clinic, and a commitment to providing patients with a broad range of prostate cancer therapies.
Seeber12 reviewed the requirements and startup costs for establishment of an APC clinic capable of administering radium-223. Seeber describes how practices can establish a hot laboratory in as little as 50 ft2 of space and with an equipment investment as low as $14,000. Regulatory approval in the form of a radioactive materials license (RML) is also needed and comprises two components: (1) facility licensure, and (2) an authorized user. The practice should confirm state requirements for an RML; apply for, or amend, facility RML to include the authorized user’s name; and ensure that the authorized user is licensed to administer parenteral therapies 35.390 or 35.396 or state equivalent. Outsourced resources are available to assist with amendments, applications, and health physics/radiation safety programs (eg, Cardinal Health Nuclear Pharmacy Services [Swedesboro, NJ], Nuclear Diagnostic Products [Cherry Hill, NJ]). Additional guidance and resources may be available from your local radiotherapy specialist.12
In addition to equipment and an RML, a clinic needs to obtain a National Institute of Standards and Technology (NIST)-traceable source from Bayer Healthcare (Wayne, NJ) and establish a dial setting for radium-223 on the dose calibrator. A radioisotope dose calibrator calibrated with an NIST-traceable radium-223 standard is necessary for dose calibration before and after administration. No instrument dedicated to α-emission detection is needed as photon emissions associated with radium-223 decay are measured using standard equipment (eg, dose calibrator, γ detector).13 Additional steps required include a credit check and addition of the practice RML to a site-licensing database.
Each phase of radium-223 use is marked by its challenges and goals. In the integration phase, goals include developing and implementing practice-wide protocols to identify radium-223 patients; identifying key metrics for assessing performance, and reviewing them regularly; and, establishing a prostate cancer committee to monitor and assess performance, including overall care.
In the integration phase, the APC clinic can have varying relationships with other practice locations and/or colleagues regarding patient referral, communication, and collaboration. Moving from the integration phase to the normalization phase requires improving referral practices, communication, analytics, and collaboration.
As practices move from the start-up to the integration phase, they often grapple with questions related to internal referral to their APC clinic. Issues include whether the referral will be encouraged or mandated, criteria/thresholds for referral, consistent patient communication when referred to the APC clinic, referring physicians’ desires to remain involved with the patient’s overall care, and administrative and business considerations.
Practices may find it helpful to create simple dashboards to assess and enhance performance. Dashboard data may include the number of patients with APC in overall practice, the number of patients with APC referred to the APC clinic, patients on various prostate cancer therapies, and radium-223 doses administered in the past month and scheduled for the month ahead.
Monthly tumor boards or similar meetings enable the prostate cancer team to review clinical status of current patients, discuss patients within the larger practice who may warrant referral to the APC clinic, and maintain physician communication. Inviting physicians from the entire practice to attend tumor board sessions can provide those physicians with insights into the APC clinic’s work and facilitate a collegial, collaborative approach to care.
At Delaware Valley Urology, our practice of >30 urologists, men can be internally referred to our APC clinic. To do this, a non-APC physician initiates a conversation with one of our operational champions who then communicates with the patient and clinical champion to expedite care. We also have worked to develop analytics to identify and prompt referrals to our APC clinic in men newly diagnosed with metastatic prostate cancer and those with CRPC.
Several indicators can signify that a practice is ready to move from the integration phase to the normalization phase, and to pursue new goals accordingly. Signs that a practice may be ready to make this shift include the following: (1) champions operating as a cohesive unit; (2) a functional practice model for administering radium-223 that is proven over time; and (3) identification and management of clinical, business, and operational challenges.
Goals for the normalization phase vary somewhat from practice to practice, but may include developing the next wave of champions throughout the practice, further speeding the identification and referral of candidates for radium-223, further incorporation of electronic medical record (EMR) and data analytics to optimize care, and making physicians and patients throughout the area more aware of the services offered by the practice’s prostate cancer clinic.
In the normalization phase, the APC clinic receives regular, timely referrals from all other clinics or locations within the larger practice, and communicates and collaborates effectively with each of them. Further, clinical, operational, and other champions are in place at the satellite locations and work in conjunction with the APC clinic’s four champions.
One of the hallmarks of the normalization phase is an enhanced approach to patient identification. Efforts in this regard may include using software tools to scan the EMR for indicators of disease progression, training clinical staff on identifying disease progression, and utilization of patient-completed surveys.
Numerous challenges are associated with detecting symptoms related to bone metastases and disease progression. These include inadequate protocols for monitoring and responding to indicators of disease progression such as rising PSA levels, evidence of bone metastases on imaging, and symptoms from bone metastases such as pain, inconsistent scanning protocols for disease progression, lack of communication between the practice’s physicians and other staff, and patient underreporting of symptoms.
Asking a patient open-ended, focused questions is one component of enhancing identification of patients who may be progressing. Asking a patient “How are you doing?” often will not elicit a response any more revealing than, “Fine.” Use of more focused questions, such as the following, is encouraged:
A potentially useful tool is to identify a patient’s favorite activities, and note them in his chart (eg, plays 18 holes of golf twice weekly). At each subsequent visit, ask about whether and to what extent, the patient continues to engage in that activity. Changes may signal disease progression.
Advancing along the spectrum of radium-223 adoption requires understanding the utility of radium-223 for your patients and your practice, identifying champions within your practice, and continuously applying key learnings. Establishment of an APC clinic requires collaboration, leadership, and practice-wide endorsement. Using the model described we have successfully established an APC clinic to administer advanced therapeutics, including radium-223.