Nuts and Bolts of ²²³Ra-Dichloride Therapy

PATIENT SELECTION, CLINICAL CONSIDERATIONS, AND PROTOCOL

The Food and Drug Administration approved use of ²²³Ra-dichloride for treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Castration-resistant cancer is cancer that continues to grow even when the testosterone levels are at or below the castrate level; it is also known as hormone-refractory or hormone-resistant prostate cancer (19). Careful screening of prior imaging for visceral metastatic disease in organs and lymph nodes is helpful; the package insert advises an upper limit of 3 cm for lymph nodes (14). Clinical guidelines indicate that patients should undergo CT of the chest, abdomen, and pelvis (if not already performed) before therapy to assess for visceral metastatic disease (20). Prostate bed disease or localized involvement of the urinary bladder is not considered visceral disease (20). Hematologic analysis must also be performed if the patient does not have visceral metastases and is being considered for therapy. Per the package insert, before the first treatment the absolute neutrophil count should be at least 1.5 × 10⁹/L, the platelet count at least 100 × 10⁹/L, and the hemoglobin at least 10 g/dL (14). Blood work should be done within at least 30 d of the initial therapy (20). There is some expected impact on bone marrow, and the patient will need follow-up blood count analysis before additional therapies. For subsequent administration of the radionuclide therapy, the patient should have an absolute neutrophil count of 1 × 10⁹/L and a platelet count of 50 × 10⁹/L; no hemoglobin limit is required for subsequent therapies (Table 1) (14).

Because this therapy localizes to regions of bony turnover, it is imperative that a patient undergo bone scanning before being considered for therapy. If the osseous metastases do not take up tracer, the patient will not benefit from this therapy and should not receive it. Pretherapy bone scans can be done with SPECT or PET bone scanning agents. Clinical guidelines indicate that there should be at least 2 osseous metastatic lesions (20). PET agents such as prostate-specific membrane antigen and fluciclovine are not a substitute for bone-seeking tracers in this setting (21).

Increasingly, nuclear medicine professionals are seeing patients in consultation before therapies and are using evaluation and management codes. This change is beneficial for patients, as they are not seen only on the day of therapy but rather have time to prepare for potentially unexpected radiation safety instructions. Consultations also allow patients or caregivers to ask questions and may ease patient concerns about the therapy and its side effects. Nuclear medicine professionals also benefit by having time to review the patient’s history; coordinate with the urologist, oncologist, or other clinical colleagues who referred the patient; and obtain insurance preauthorization. During the consultation process, needed items can be identified, such as a bone scan or blood work, which can then be obtained in a timelier manner so as not to delay care or result in a wasted therapy dose.

Understanding prior therapies the patient has had is also important. ²²³Ra-dichloride when given in conjunction with abiraterone therapy + prednisone or prednisolone has been associated with an increased frequency of fractures, compared with patients who did not receive the ²²³Ra-dichloride (22). This association has caused the European Medicines Agency to recommend a contraindication in this setting. This recommendation is not reflected in the Food and Drug Administration’s package insert at this time, but nonetheless, current guidelines discourage this practice (20). Other myelosuppressive therapies the patient may have had in the 4 wk before therapy may also set the patient up for more profound myelosuppression. Likewise, if patients have had external-beam hemibody radiation or other systemic radionuclides within 24 wk of therapy, careful consideration of the risk-to-benefit ratio of therapy is recommended (20). If patients have epidural tumor or spinal cord compression, they should be treated preferentially with external-beam radiation therapy before ²²³Ra-dichloride (20). Working together with clinical colleagues to settle on an appropriate time for ²²³Ra-dichloride therapy is important.

Assessing performance status is recommended. This assessment can be done with the Eastern Cooperative Oncology Group or Zubrod performance status criteria (23). Guidelines suggest that life expectancy should be at least greater than 6 mo, and an Eastern Cooperative Oncology Group performance status of 0 to 2 is preferred (20). Guidelines also recommend documentation of pain and patient-related symptoms before and during therapy to evaluate the patient’s quality of life (20,22).

Because of the complexity of tracking the many elements of therapy, it can be helpful to use a checklist for each patient. Example items to keep on such a checklist are in Table 2.

Provided the patient meets the laboratory parameters and functional status requirements, therapy is given intravenously every 4 wk for a total of 6 therapies. If there is evidence of myelosuppression after a therapy, the next therapy can be delayed for to up to 6–8 wk. If blood counts do not improve despite supportive care, no further treatment is given (14). Table 3 reviews important clinical metrics to evaluate before therapy. Figure 1 illustrates the therapy procedure at a glance.

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FIGURE 1.

Therapy process. CBC = complete blood count; diff = differential.

RADIOPHARMACEUTICAL THERAPY PROPERTIES AND DOSIMETRY

²²³Ra is an α-particle and has a half-life of 11.43 d. Most of the therapy (95.6% abundance) is α-particles, which deposit high energy with a very short pathlength. β-particles make up 3.6% of the decay, and γ-photons make up 1.1% (14). These γ-photons allow for easy measurement on standard dose calibrators and survey meters. The full decay schema is described in Figure 2, and the dosimetry is detailed in Table 4 (24). Given the dosimetric data, one can understand why gastrointestinal symptoms may occur, as the radiopharmaceutical is excreted predominantly via the gastrointestinal tract in healthy individuals.

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FIGURE 2.

Decay schema for ²²³Ra-dichloride.

RADIATION SAFETY PRECAUTIONS, PATIENT CONSENT, AND AS-NEEDED MEDICATIONS

According to the Nuclear Regulatory Commission, all radionuclide therapies should be given under the auspices of a quality management program (20). A written directive is required for each ²²³Ra-dichloride therapy for each individual (i.e., 6 written directives for an individual patient for the entire course of therapy). Written directives include the administered activity, which in this case is weight-based (55.13 kBq [1.49 μCi]/kg), and an updated weight will be necessary for ordering doses a week before therapy. Once again, assessment of the complete blood count with differential will be necessary to determine whether the patient is experiencing myelosuppression and needs a pause or discontinuation of therapy.

During the clinical consultation, there should be careful discussion of the radiation safety precautions, side effects, and complications. When discussing precautions to take after the therapy, nuclear medicine professionals should primarily focus on stool and body fluids. Patients should be told to sit while urinating to minimize splatter and that careful handwashing after using the restroom is imperative. If there is a urinary catheter, patients should be told to use disposable gloves when manipulating or changing it. Instructions are also recommended on disposal of any materials that could contain body products. As part of consenting to the therapy, the patient should understand the potential side effects. The most common are myelosuppression, diarrhea, nausea, and peripheral edema. As-needed medications for nausea and diarrhea may be prescribed, or over-the-counter versions can be recommended. Patients should also be made aware of the potential for a transient increase in bone pain, often referred to as the flare phenomenon (20). Because of this potential, and because a patient may already have pain at baseline, the clinician who treats that pain should be told of the possible need for an increase in medication, so it can be arranged for in advance.

Complications that have been reported from ALSYMPCA are myelosuppression (13%), neutropenia (2%), thrombocytopenia (7%), and grade 5 treatment-emergent adverse events (13%). Long-term follow-up of patients from the trial yielded no suggestion of myelodysplastic syndrome, acute myelogenous leukemia, or new primary bone cancer. Secondary non–treatment-related malignancies occurred in 4 patients treated with ²²³Ra-dichloride, whereas 3 occurred in placebo patients. One patient experienced aplastic anemia 16 mo after the last injection (12).

DAY-OF-THERAPY TECHNICAL CONSIDERATIONS

Although external radiation exposure from ²²³Ra-dichloride is quite low compared with other therapies, care in administration is key. Care should be taken to avoid internal radiation contamination through injection, inhalation, or skin absorption. Because α-particles deposit their energy in a highly localized range, greater damage can occur than with β-particles or γ-photons. Because of the long half-life, spills should be avoided but can be identified with standard survey equipment because of the γ-photons. Contamination can be cleaned up with a dilute aqueous ethylenediaminetetraacetic acid solution, and areas can be resurveyed to ensure that they are decontaminated.

Before administration, the therapeutic dose should be measured, absorbent shielding should be placed under the patient’s arm to prevent spillage, and the intravenous catheter should be checked for patency. The therapy is often given with a 3-way stopcock with a saline flush to ensure maximal delivery; all intravenous lines and connections should be secure. Because this is an α-particle therapy, more localized damage may occur in the event of extravasation. A shield is recommended to keep the dose to the individual delivering the therapy as low as reasonably achievable. Dose rates are surprisingly high near the point source itself (Table 5). Some institutions choose to use a test dose of a small amount of ^99mTc-pertechnetate and acquire dynamic images to ensure a patent intravenous catheter. A slow intravenous injection over 1 min is used. After injection, flushing with isotonic saline is recommended (20).

CREATING A SUCCESSFUL RADIONUCLIDE THERAPY PROGRAM WITH ²²³RA-DICHLORIDE

According to the manufacturer, Bayer HealthCare, technical prerequisites for site initiation include obtaining a radioactive materials license approved for medical use of ²²³Ra-dichloride, creating an authorized-user list for medical application of ²²³Ra-dichloride, providing documentation regarding training on handling and use of ²²³Ra-dichloride, and verifying the accuracy of dose calibrators to measure ²²³Ra-dichloride activity. Dose calibrator testing with a National Institute of Standards and Technology–traceable ²²³Ra standard is provided by Cardinal Health. Additional prerequisites, which may already be established in a nuclear medicine area, include monitoring occupational doses and securing areas for storage, waste disposal, and inventory management (25).

Some studies have established data that ²²³Ra-dichloride is cost-competitive as compared with other prostate cancer therapies. In addition, ²²³Ra-dichloride therapy has been found to result in fewer skeleton-related events than other therapies, and other groups have demonstrated a slower decline of quality of life over time, with meaningful improvement, in patients who receive this therapy than in those who receive placebo (12,26).

After a site has been initiated, understanding the codes involved in billing is important (Table 6). If the therapy is administered in a hospital setting, working closely with the hospital billing office is important, as is staying attuned to potential annual changes in Centers for Medicare and Medicaid Services coding practices. Both inside and outside the hospital, Xofigo Access Services offers guidance on coding (25). Before therapy is administered, it is recommended that insurance companies be queried on the need for prior authorization. The time needed for prior authorization is quite variable among different insurance providers, but 15 or more business days may be needed. Failure to use codes can result in denial. In addition, failure to allow enough time for preauthorization or for managing clinician and patient expectations can also be problematic. To ensure that patients do not have an out-of-pocket burden, close work with institutional billing offices or Xofigo Access Services should allow them to provide guidance on issues encountered in coding and billing. In addition, the Society of Nuclear Medicine and Molecular Imaging website has a “Coding and Reimbursement Q&A” section with resources available to members (27).

In addition to these items, it is imperative to provide patients with multidisciplinary care and identify clinicians of various backgrounds who will be involved in therapy referral and follow-up. Follow-up practices may differ on the basis of institutional protocols. Some practices include mid-therapy evaluation with laboratory biomarkers or imaging; however, no well-defined guidelines exist yet.

LOOKING AHEAD

The use of ²²³Ra-dichloride is likely to evolve, considering the recent Food and Drug Administration approval of ¹⁷⁷Lu-vipvotide tetraxetan (also known as ¹⁷⁷Lu-PSMA-617) (28). ²²³Ra-dichloride is a bone-based therapy, whereas ¹⁷⁷Lu-vipvotide tetraxetan is a therapy that can also target soft-tissue lesions. Holistic evaluation and the tracer uptake profile of the patient may be needed to assess which agent would be of most benefit.

Another area of interest may be repeat ²²³Ra-dichloride therapy. Some research has already been done in this area, and the findings suggest that the therapy is well tolerated and provides additional control of osseous metastatic disease (29,30). Longer-term follow-up may be helpful to evaluate for continued long-term safety.

EDUCATION AND RECOMMENDED READING

There is a good deal of helpful information available to those starting a ²²³Ra-dichloride therapy program. Some of the higher-yield materials include the ²²³Ra practice parameters of the American College of Radiology, American College of Nuclear Medicine, American Society for Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging (20); the ALSYMPCA trial (12); and Xofigo access services (25).

DISCLOSURE

No potential conflict of interest relevant to this article was reported.