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Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer

Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer

Table 1: Overview of Study Design in Studies of Agents That Showed Red...
Table 2: Hazard Ratios for Time to First Skeletal-Related Event (SRE) ...
Table 3: Dose, Schedule, and Duration of Treatment for Agents Used to ...
Table 4: Agents Used to Reduce Skeletal-Related Events in Metastatic C...

Skeletal-related events contribute substantially to morbidity, mortality and cost in men with metastatic castration-resistant prostate cancer (mCRPC). There are five agents available for treatment in mCRPC that reduce skeletal-related events. Here we discuss the efficacy and safety of zoledronic acid, denosumab, enzalutamide, abiraterone, and radium-223. We include data on and a discussion of duration of treatment with zoledronic acid and denosumab, the only two of these agents that do not have a clinically proven anticancer effect. Finally, we review the available data regarding the cost of denosumab compared with that of zoledronic acid.

Epidemiology

In 2015, an estimated 220,800 US men will be diagnosed with prostate cancer and 27,540 will die of the disease, making prostate cancer the most common nondermatologic cancer in men and the second most deadly.[1] Among men who develop metastatic prostate cancer, up to 90% will have osseous metastases.[2]

Definitions of SRE and SSE

Osseous metastatic disease is common in metastatic prostate cancer and typically occurs in the axial skeleton and/or proximal appendicular skeleton, possibly because these bones contain hematologically active bone marrow.[3] Prostate cancer osseous metastases stimulate osteoblasts, resulting in blastic osseous metastases and elevated levels of serum alkaline phosphatase.[4] Events that occur because of osseous metastases are termed “skeletal-related events” (SREs) and include pathologic bone fractures, spinal cord compression, orthopedic surgery interventions, and palliative radiation to the bone. Some studies also include in the SRE definition change in neoplastic therapy secondary to bone pain. SREs may be detected clinically on the basis of symptoms or by reviewing imaging; detection via imaging is possible whether or not an SRE causes symptoms. Symptomatic skeletal events (SSE) use a slightly different definition that limits these to events that affect the patient experience. This definition was first used in the pivotal Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, where SSEs included external beam radiation therapy to relieve bone pain, occurrence of new symptomatic pathologic fractures (vertebral and nonvertebral), occurrence of spinal cord compression, or tumor-related orthopedic interventions. Even when the SRE definitions are similar, their measurement may differ: eg, some studies have included routing skeletal radiography to detect asymptomatic events, while others have not.

Clinical Significance of SREs

SREs are associated with increased mortality and cost. In an examination of 194 patients with prostate cancer treated with androgen suppression therapy, 24 experienced a fracture after their diagnosis. Overall survival was significantly decreased in these patients compared with survival in those without fracture: median overall survival was 121 months in men with a fracture and 160 months in those without (P = .04).[5] A recent publication examined inpatient billings (from the Nationwide Inpatient Sample [NIS]) for SREs between 1998 and 2010 and found that the inpatient cost of SRE had increased by 94% over that period—to $369,256,799.[6] However, the rate of SRE decreased from 18% to 15.4%, and SRE-associated mortality also decreased, from 8.5% to 4.7%. The authors hypothesize that the markedly increased cost of treating SREs (relative to the rate of SRE) is related to inflated costs of the treatments for SRE, as well as the costs of treating comorbid conditions in affected patients.

Ways of Assessing SREs

Pathologic fracture

Detection of pathologic fracture—and the time to detection—in a clinical trial varies depending on the imaging modality used and on the frequency of imaging, respectively. Different types of imaging studies have different sensitivities for fracture, and the particular study used has varied from trial to trial. In some studies, prostate cancer patients received scheduled skeletal surveys that included plain films of the skull, spine, chest, pelvis, arm from shoulder to elbow, and leg from hip to knee.[7,8] The sensitivity of plain films for fracture varies depending on location, and they are likely to miss occult fractures.[9] Skeletal surveys are not commonly used in the management of prostate cancer, so their real-world applicability is limited. In most studies, nuclear medicine bone scans with technetium-99 were used. The sensitivity of a nuclear medicine bone scan for fractures is high; for example, such a scan has a sensitivity of 98% for an occult hip fracture.[9] However, bone scans also show blastic osseous metastatic disease, which could hide a fracture, given that fractures often occur in bones weakened by tumors. In studies that only required bone scans, fractures were likely detected by other means, such as CT scan or plain films that were ordered to follow up on pain. The frequency of imaging studies affects time to detection of pathologic fracture. Most of the studies included visits with patients every 4 weeks and imaging every 12 weeks.

Spinal cord compression

The most common presenting symptom for spinal cord compression is pain followed by neurologic changes.[10] Diagnosis often requires an MRI or CT myelogram.

Orthopedic surgery to the bone

This is detected by a review of patient records.

Palliative radiation to the bone

This is also detected by a review of patient records. Subjectivity is involved in the determination of this SRE, since pain in the bone may lead one clinician to refer a patient to radiation oncology, while another clinician might respond to the same complaint by changing the antineoplastic regimen.

Change of antineoplastic therapy for bone pain

This is also detected by a review of patient records. In addition, with this SRE, the investigator is required to document the reason that a change in therapy was made.

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