NcXHF

DORFF AND GROSS
223 may confer fewer benefıts when administered fırst, before
docetaxel as well as against the theoretical concern for
compromised marrow reserve affecting future docetaxel
therapy. Data are still awaited to answer these questions with
greater certainty. However, given the relatively mild myelosuppression
and previous experience with samarium in combination
with docetaxel, combination therapy is undergoing
study (NCT01106352). In the phase I experience of radium
223 and docetaxel, substantial hematologic toxicity limited
administration of full doses and thus further combination
studies will utilize a reduced dose of docetaxel 60 mg/m 2 . 6
Another signifıcant concern when the potential for earlier
administration is considered is the risk of secondary myelodysplasia.
Very limited long-term data are currently available.
The long-term report presented at 2014 American
Society of Clinical Oncology Genitourinary Cancers Symposium
consisted of median follow-up of 10.4 months. 7 At that
time point, no myelodysplastic syndrome or acute myeloid
leukemia had been reported, and secondary solid tumors
were similar in the radium 223 and placebo arms. However,
longer follow-up will be critical to address this concern.
Much less is known about the timing and interaction between
radium 223 and the newer antiandrogen agents (abiraterone
or enzalutamide). Both agents have demonstrated
noteworthy clinical activity defıned by increases in overall
survival in patient subsets defıned by the presence of cancerrelated
bone pain. Further, both agents have shown important
benefıts in quality-of-life measures including palliation
in bone pain or delay to skeletal-related events in certain patient
subpopulations. 8,9 ALSYMPCA allowed standard care,
including ketoconazole and older androgen receptor antagonists,
but this cannot be extrapolated to assume that newer
agents such as abiraterone and enzalutamide can be safely
combined with radium 223. No data exist to suggest that
combination use is superior to single sequential therapy. The
open-access protocol did allow abiraterone, and the safety
and effıcacy of these combinations will be formally evaluated
in an ongoing clinical trial (NCT02034552).
DURATION
Just as questions emerge as to the optimal timing for initiation
of radium 223 dichloride, many questions also arise as to
when it should be discontinued. The approved treatment
course is 6 monthly doses, although the relative effıcacy and
tolerability of fewer or more doses is not well established. At
the time of the New England Journal of Medicine publication
from the ALSYMPCA trial, 3 42% of patients on the radium
223 arm had not received all 6 doses although the median
number of doses was 6; updated data regarding clinical factors
associated with completion of the treatment course may
be helpful. The phase I study evaluated a single dose in patients
with breast and prostate cancer with bone metastases
and the phase II study in prostate cancer gave 4 doses at
monthly intervals, 10,11 but there is no way to evaluate what
number of doses is optimal from the available data. Given
that no cumulative toxicities were seen with 6 monthly doses,
and the rate of hematologic toxicities was tolerable, it is reasonable
to explore the effect of additional dosing on disease
control and the duration of pain palliation. The effect of extended
therapy with up to 6 additional doses, or a total of 12
doses of radium 223, is being evaluated in a clinical trial
(NCT01934790). Additionally, we do not have data about retreatment
of patients who were previously treated. Thus at
this time no conclusions can be made as to the effıcacy nor
safety of more than 6 monthly doses of radium 223.
Effectiveness may be diffıcult to gauge during the nominal
6-month treatment period. Prostate-specifıc antigen (PSA) is
an unreliable marker of response to radium 223 as it often
continues to increase (unabated) during the treatment independent
to the effect on overall survival. In the ALSYMPCA
trial the median time to PSA progression was 3.6 months for
men in the radium 223 arm compared with 3.4 months in the
control arm (HR 0.64; 95% CI, 0.54 to 0.77) and 16% achieved
a PSA decline at 12 weeks compared with 6% of control patients.
These PSA changes must be viewed in the context that
the patients could receive additional standard therapy (in
ALSYMPCA, standard care could include antiandrogens, ketoconazole,
estrogens, and external beam radiotherapy).
Nevertheless, discontinuation of radium 223 in patients with
rising PSA but no clinical disease progression is not indicated,
and rather application of additional standard therapy
may be considered. Thus, even in patients without early pain
relief from radium 223 or with rising PSA, it may be preferable
to add external beam radiotherapy or additional systemic
therapy, and proceed through the course of 6 doses
rather than stopping therapy early.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Tanya Dorff, Astellas Pharma, Bayer, Dendreon,
Medivation, Pfizer, Sanofi. Consulting or Advisory Role: Tanya Dorff, Dendreon. Speakers’ Bureau: Tanya Dorff, Bayer, Medivation, Pfizer. Research
Funding: Tanya Dorff, Bristol-Myers Squibb. Mitchell Gross, Novartis, Janssen Biotech. Patents, Royalties, or Other Intellectual Property: None. Expert
Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
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