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2017; 63(12):1019-1023
D
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extraction
Survival
After evaluating 64 mCRPC patients eligible for radiation
therapy due to bone pain, with mean follow-up time of
18 months, there was greater survival among patients
treated with Ra223 (50 kBq/kg dosage) compared to a
placebo. Median survival was 65.3 versus 46.4 weeks, re-
spectively, significantly higher for Ra223 (50 kBq/kg dos-
age) (p=0.006) compared to a placebo (HR=2.12, 95CI
1.12-3.98; p=0.020), indicating a higher risk of death
for the placebo group.
3
(
A
) After 2 years of follow-up of
these patients, the median survival of the Ra223-treat-
ed group was 71 weeks versus 46.4 weeks in the placebo
group (HR=0.445, 95CI 0.232-0.851).
4
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In the largest phase III multicenter controlled ran-
domized trial evaluating 921 mCRPC patients, 614 re-
ceived six injections of Ra223 (50 kBq/Kg dosage) and
307 received placebo injections. Those patients treated
with Ra223 had greater survival compared to those treat-
ed with placebo, with a median survival of 14.9 versus
11.3 months. The absolute increase in survival was 10.5
months (95CI 3.3-17.7). In this case, it is necessary to treat
nine patients to have an increase in survival of 3.6 months
(on average) in one patient.
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When this same population was stratified according to
prior use of docetaxel, Ra223 continued to show an increase
in survival, both in the group of prior use (HR=0.70, 95CI
0.56-0.88; p=0.002) compared to the group that had never
used docetaxel (HR=0.69, 95CI 0.52-0.92; p=0.01).
6
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Bone event
In an initial study with 64 mCRPC patients, there was
longer time until the first bone event in the Ra223-treat-
ed group compared to the placebo group (14 weeks versus
11 weeks) (HR=1.75, 95CI 0.96-3.19; p=0.065). However,
there was no significant difference in the number of bone
events (p=0.625).
3
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B
)
In the large ALSYMPCA study, evaluating 921 patients
with mCRPC, patients treated with Ra223 had longer
time until the first bone event compared to the placebo
group. Median time until the first bone event was 15.6
months with Ra223 versus 9.8 months with a placebo
(HR=0.66, 95CI 0.52-0.83; p<0.001).
5
(
A
)
The data from the above study were further analyzed,
focusing exclusively on the skeletal events of the mCRPC
population.
7
(
A
) The authors demonstrated that symp-
tomatic skeletal events occurred in 33% of patients in
the Ra223 group and 38% in the placebo group. The
Ra223 group required less use of radiotherapy to treat
pain (HR=0.67, 95CI 0.53-0.85) and presented a lower
spinal compression rate (HR=0.52, 95CI 0.29-0.93). De-
spite this, the use of Ra223 did not significantly reduce
the risk of occurrence of bone events (HR=0.62, 95CI
0.35-1.09) nor the risk of surgical interventions (HR=0.72,
95CI 0.28-1.82).
7
(
A
)
Another study stratified the population described
above according to prior use of docetaxel or not. 352
patients who used docetaxel prior to Ra223 were evalu-
ated versus 262 patients who used only Ra223. There was
a reduction in time until the first bone event only in the
group of patients taking Ra223 who had previously used
docetaxel (p=0.0009).
6
(
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)
D
ose
toxicity
and
safety
In the initial randomized controlled multicenter phase
II trial of 64 mCRPC, with patients divided into Ra223
and placebo groups, there was no significant difference
in hematological toxicity. In addition, no patient discon-
tinued treatment for this reason.
3
(
A
)
The use of different doses of Ra223 (5 kBq/kg in 26
patients; 25 kBq/kg in 25 patients; 50 kBq/kg in 25 pa-
tients; 100 kBq/kg in 24 patients) in 100 mCRPC patients
showed no difference in adverse effects among the groups
analyzed, and 97% of the patients reported at least one
adverse effect. Adverse effects included nausea, fatigue,
vomiting, diarrhea, constipation, bone pain, urinary tract
infection and peripheral edema.
8
(
A
)
Then, another study with a slightly larger casuistry
(122 patients) was conducted to evaluate the efficacy and
safety of different dosages of Ra223. The doses admin-
istered were 25 kBq/kg in 41 patients, 50 kBq/kg in 39
patients and 80 kBq/kg in 42 patients, each of them
undergoing a protocol of three applications every 4 weeks.
The study demonstrated that dosages up to 80 kBq/Kg
are safe. Ninety-two per cent (92%) of the patients had at
least one adverse effect: diarrhea (21%), nausea (16%) and
anemia (14%). There were no differences among the groups
regarding survival, bone events, pain reduction or hema-
tological events.
9
(
A
)
In the ALSYMPCA study (N=921), the overall num-
ber of adverse and hematological effects was lower in
patients treated with Ra223 (93%) compared to placebo
(96%), with 47% serious events in the first and 60% in the
latter group. The number of grade 3 or 4 adverse hema-
tological effects was not significantly higher in the group
treated with Ra223.
5
(
A
)
Subgroup analysis of ALSYMPCA patients stratified
by prior docetaxel use showed that the incidence of grade
3 or 4 anemia and neutropenia was similar between Ra223
and placebo, regardless of previous use of docetaxel.
6
(
A
)