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DORFF AND GROSS
Radium 223: How Can We Optimize This New Tool for
Metastatic Castration-Resistant Prostate Cancer?
Tanya Barauskas Dorff, MD, and Mitchell E. Gross, MD, PhD
OVERVIEW
Radium 223 is an alpha-emitting intravenous radiotherapy approved for the treatment of men with metastatic castration-resistant
prostate cancer (mCRPC). The approved indication covers men with pain from bony metastatic disease and no visceral involvement;
however, questions remain as to optimal patient selection and timing of this treatment relative to other life-extending therapies for
mCRPC. Limited data exist to guide clinicians on how to position radium 223 in the therapeutic sequence, however, some theoretical
considerations and data derived from the ALSYMPCA trial populations pre- and postdocetaxel will be outlined. Subgroup analyses may
provide some insight into patient selection.
Radium 223 is a calcium-mimetic alpha-emitting radiopharmaceutical
that was approved by the U.S. Food
and Drug Administration for the management of mCRPC
in 2013. Unlike previous radiopharmaceuticals, such as
samarium-153-lexidronam and strontium chloride Sr 89 that
provide pain palliation without having a known effect on survival,
1,2 radium 223 has been found to prolong survival in patients
with mCRPC. 3 The approved dosing of radium 223 is 50
kBq/kg given intravenously over 1 minute every 28 days for 6
doses. Questions remain as to its optimal application, particularly
in terms of patient selection and sequencing of this therapy
relative to other approved life-extending therapies for mCRPC.
There are a paucity of real-world data, and key limitations for
the use of radiopharmaceuticals include special licensing requirements
to administer therapy and lack of comparative data.
Ongoing studies aim to address questions of sequence and combination,
but we will discuss patient selection and timing for radium
223 therapy in the context of the limited available data.
WHICH PATIENTS?
The ALSYMPCA trial randomly assigned 928 men with pain of
any intensity related to bone metastases from mCRPC and
whose disease had either progressed on docetaxel or who were
not docetaxel candidates, to receive 50 kBq/kg of radium 223
intravenously over 1 minute each month for 6 doses or placebo
IV each month for 6 doses in conjunction with standard care
(Table 1). 3 Men with known visceral metastases were excluded,
but malignant lymphadenopathy smaller than 3 cm in short axis
diameter was allowed. Adequate hematologic function is required.
Before the fırst administration of radium 223, the absolute
neutrophil count was 1.5 10 9 /L or higher, the platelet
count was 100 10 9 /L or higher, and hemoglobin was 10 g/dL
or higher. Before subsequent administrations of radium 223, the
absolute neutrophil count was 1 10 9 /L or higher and the platelet
count was 50 10 9 /L or higher. The primary endpoint was
overall survival and the main secondary endpoint was time to
symptomatic skeletal-related event (sSRE). Most patients (58%)
had received docetaxel, and 41% had received bisphosphonate
therapy.
A signifıcant increase in overall survival was observed
across all patients treated with radium 223 (hazard ratio [HR]
0.7; 95% CI, 0.58 to 0.83; p 0.001), however, analysis of
subsets may help clarify the characteristics of optimal candidates
for this treatment based on blood or imaging biomarkers.
Serum alkaline phosphatase, one marker of overall
osteoblastic activity, did seem to defıne patients who benefıted
the most from radium 223 treatment. Specifıcally, no
increase in overall survival was seen in the subgroup treated
with less than 220 U/L of serum alkaline phosphatase. In contrast,
there was no clear separation of radium 223 benefıt according
to the extent of disease as defıned by the number of
lesions on the bone scintigraphy. Although subgroup analysis
revealed a statistically signifıcant (HR 0.95; 95% CI, 0.46 to
1.95 for 6 bone metastases; no p value given) survival benefıt
with radium 223 for men with more than six bone metastases,
the subgroups of men with two to six metastases or
superscan had confıdence intervals crossing 1, calling into question
the benefıt of therapy for these subgroups. Although small
group sizes may limit the strength of these subset analyses, the
results do validate continuing efforts to better defıne patient
groups who are most likely to benefıt from this treatment.
From the Genitourinary Cancers Program, USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Tanya Dorff, MD, Genitourinary Cancers Program, USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake
Ave. #3440, Los Angeles, CA 90033; email: dorff@usc.edu.
© 2015 by American Society of Clinical Oncology.
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