clinical experience after 532 cycles from a single institution

Eur J Nucl Med Mol Imaging (2016) 43:8–20
DOI 10.1007/s00259-015-3185-4
ORIGINAL ARTICLE
Factors affecting 223Ra therapy: clinical experience after 532
cycles from a single institution
Elba C. Etchebehere 1,2 & Denái R. Milton 3 & John C. Araujo 4 & Nancy M. Swanston 1 &
Homer A. Macapinlac 1 & Eric M. Rohren 1
Received: 7 July 2015 / Accepted: 28 August 2015 / Published online: 29 September 2015
# Springer-Verlag Berlin Heidelberg 2015
Abstract
Purpose The aim of this study was to identify baseline features that predict outcome in 223Ra therapy.
Methods We retrospectively reviewed 110 patients with metastatic castration-resistant prostate cancer treated with 223Ra.
End points were overall survival (OS), progression-free survival (PFS), bone event-free survival (BeFS), and bone marrow
failure (BMF). The following parameters were evaluated prior
to the first 223Ra cycle: serum levels of hemoglobin (Hb),
prostate-specific antigen (PSA), alkaline phosphatase (ALP),
Eastern Cooperative Oncology Group (ECOG) status, pain
score, use of chemotherapy, and external beam radiation therapy (EBRT). During/after 223Ra we evaluated: the total number
of radium cycles (RaTot), the PSA doubling time (PSADT), and
the use of chemotherapy, EBRT, abiraterone, and enzalutamide.
Results A significant reduction of ALP (p<0.001) and pain
score (p=0.041) occurred throughout the 223 Ra cycles. The
risk of progression was associated with declining ECOG status [hazard ratio (HR) = 3.79; p < 0.001] and decrease in
PSADT (HR=8.22; p<0.001). RaTot, ALP, initial ECOG status, initial pain score, and use of abiraterone were associated
with OS (p≤0.008), PFS (p≤0.003), and BeFS (p≤0.020).
RaTot, ALP, initial ECOG status, and initial pain score were
significantly associated with BMF (p≤0.001) as well as Hb
(p<0.001) and EBRT (p=0.009). On multivariable analysis,
only RaTot and abiraterone remained significantly associated
with OS (p<0.001; p=0.033, respectively), PFS (p<0.001;
p=0.041, respectively), and BeFS (p<0.001; p=0.019, respectively). Additionally, Ra Tot (p = 0.027) and EBRT
(p=0.013) remained significantly associated with BMF.
Conclusion Concomitant use of abiraterone and 223Ra seems
to have a beneficial effect, while the EBRT may increase the
risk of BMF.
Keywords Prostate cancer . 223Ra . PSA . Bone marrow
failure . Abiraterone . External beam radiation therapy
Introduction
* Elba C. Etchebehere
[email protected]
1
Department of Nuclear Medicine, The University of Texas MD
Anderson Cancer Center, 1400 Pressler, FCT 16.6005, Unit 1483,
Houston, TX 77030, USA
2
Department of Nuclear Medicine, Campinas State University
(Unicamp), Rua Vital Brasil, 251, Cx.Postal. 6142, Cidade
Universitária Zeferino Vaz, 13083-888, Campinas, Brazil
3
Department of Biostatistics, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA
4
Department of Genitourinary Medical Oncology, The University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Radium dichloride therapy (223Ra) is gaining widespread use
in patients with symptomatic bone metastases from castrationresistant prostate cancer (mCRPC) due to its demonstrated
survival benefits [1–3]. However, outside of controlled regulatory trials, the algorithm and therapeutic approach of this
novel radiopharmaceutical are not well established.
Bone-related parameters are typically used to predict overall survival (OS) in mCRPC patients [4]. Worst survival is
observed in patients with hemoglobin (Hb) levels below
10 g/dl, prostate-specific antigen (PSA) levels above 10 ng/ml,
alkaline phosphatase (ALP) levels above 146 U/l, pain scores
above 3 (according to the WHO criteria), the presence of
skeletal-related events, patients with older age, and patients
with visceral metastases. However, when managing mCRPC
Eur J Nucl Med Mol Imaging (2016) 43:8–20
patients in the compassionate scenario, many (if not all) of the
bone-related parameters frequently used to determine outcome denote dismal survival in all patients, and thus the discrimination of which patients benefit from therapy in terms of
OS, progression-free survival (PFS), marrow depletion, and
skeletal-related events is more difficult. As a result, there is a
need to identify factors that will predict outcome, especially
for new therapies, like 223Ra.
Given that the therapeutic approach of 223Ra is not well
established in clinical practice, to obtain the full benefit of this
novel therapy in mCRPC patients, there is a need to establish
the optimal time to perform 223Ra as these patients with rapidly progressing tumors may not have sufficient time for marrow recovery prior to their next 223Ra treatment. Likewise, it is
important to determine which factors, such as combined therapies and disease status, may influence 223Ra treatment.
Although there have been previous reports on 223Ra with a
limited number of patients and with a short follow-up [5], to
our knowledge there have not been reports from a single institution with a large number of patients treated with 223Ra outside a regulatory trial. Consequently, it is not clear where 223Ra
should be placed in the treatment algorithm for mCRPC patients, especially in the clinical setting of a compassionate use
program. The purpose of this study was to determine the factors
that may predict outcome in patients undergoing 223Ra therapy.
Materials and methods
Study design
This retrospective study was approved by our Institutional
Review Board (PA14-0848). The waivers of informed consent
and authorization were granted for the retrospective analysis.
We reviewed records of consecutive patients with histologically confirmed mCRPC treated with 223Ra between July 2013
and March 2015.
Clinical and laboratory evaluation prior to 223Ra
Clinical evaluation prior to 223Ra consisted of determining the
patient’s Eastern Cooperative Oncology Group (ECOG) performance status and pain scores (according to WHO criteria)
(Table 1).
Laboratory tests prior to 223Ra involved assessing the patient’s hematologic status and the dynamics of the disease.
These consisted of serum concentrations of Hb, platelets
(PLT), absolute neutrophil counts (ANC), ALP, and PSA.
Laboratory parameter cutoff values established to determine
the ability to predict survival [4, 6] were as follows: Hb <10 g/
dl vs ≥10 g/dl, ALP ≥146 UI/l vs <146 UI/l, and PSA
>10 ng/ml vs≤10 ng/ml. The clinical and laboratory parameters evaluated prior to the first 223Ra cycle were: Hb, PSA,
9
ALP, ECOG status, pain scores, and the use of chemotherapy
and external beam radiation therapy (EBRT). During and/or
after the 223Ra cycles the clinical and laboratory parameters
assessed were: total number of radium cycles (RaTot) and use
of chemotherapy, EBRT, abiraterone, and enzalutamide. In
addition, PSA doubling time (PSADT) was computed between
two 233Ra cycles and the cutoff used to predict survival was
<3 months vs ≥3 months.
Imaging evaluation prior to 223Ra
Imaging studies were performed on all patients prior to 223Ra.
These studies consisted of one or more of the following in
order to determine eligibility for 223Ra therapy and/or to restage the patients: whole-body skeletal 18F-fluoride positron
emission tomography (PET)/CT scan (69.1 %), whole-body
metabolic 18F-fluorodeoxyglucose (FDG) PET/CT scan
(23.6 %), and whole-body conventional bone scintigraphy
(7.3 %). In addition, some patients had CT scans and MRI
scans per standard clinical practice. In some cases, biopsy
was performed in order to determine the etiology of equivocal
lesions, again based on clinical decisions.
Skeletal tumor burden was classified as low, intermediate,
and high burden. In patients imaged with 18F-fluoride PET/CT
scans and whole-body conventional bone scintigraphy, skeletal tumor burden was classified as low when the number of
bone metastases was less than 20, intermediate when the number of bone metastases was between 20 and 50, and high when
the number of bone metastases was above 50 or in the presence of diffuse disease (superscan). On whole-body metabolic
18
F-FDG PET/CT scans the metabolic tumor burden was classified as low when the number of metabolically active bone
metastases was less than 6, intermediate when the number of
bone metastases was between 6 and 20, and high when the
number of bone metastases was above 20.
Determination of outcome measures
The primary end point was OS, which was established from
initial 223Ra dose until date of death from any cause or last
follow-up. Patients alive at the last follow-up date were censored. Secondary end points were PFS, bone event-free survival (BeFS), time to progression (TTP), and bone marrow
failure (BMF). Patients who were alive and did not experience
an event (progression, bone event, or BMF) were censored.
PFS was established from initial 223Ra cycle until date of
objective tumor progression, death of any cause, or last follow-up. Objective tumor progression was defined as a lesion
progressing in the bone or soft tissue (nodal or visceral lesions) leading to a change in current therapy or initiation of
another therapy (chemotherapy, radiation therapy, or secondary hormone therapy). TTP was assessed from the date of
initial 223Ra cycle to date of objective tumor progression.
10
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Table 1 Classification of ECOG
status, pain score, and
hematologic toxicity
ECOG status
0
Asymptomatic: fully active, able to carry on all activities without restriction
1
2
3
4
Symptomatic: restricted in physically strenuous activity; able to carry out work of a light
or sedentary nature
Symptomatic: <50 % in bed during the day; ambulatory and capable of all self-care;
unable to carry out any work activities
Symptomatic: >50 % in bed; capable of only limited self-care, confined to bed or chair
50 % or more of waking hours
Bedbound
5
Death
Pain score (according to WHO criteria)
0
No pain; analgesia not required
1
2
Mild pain; no opioid use
Moderate pain with occasional opioid use
3
Severe pain with daily opioid use
Hematologic toxicity (according to WHO criteria)
Hb (g/dl)
1
>10.0
2
8.0 to<10.0
3
4
<8.0 (transfusion indicated)
Life-threatening; urgent intervention indicated
ANC (/mm3)
>1,500
1,000 to<1,500
Platelets (/mm3)
>75,000
50,000 to<75,000
500 to<1,000
<500
25,000 to<50,000
<25,000
ANC absolute neutrophil counts
BeFS was defined from initial 223Ra cycle until the date of an
objective skeletal-related event, characterized as a surgical
intervention, spinal cord compression, pathologic fracture,
bone pain or rapid lesion progression requiring immediate
intervention, death of any cause, or last follow-up. BMF was
assessed from the date of last 223Ra cycle to date of BMF.
BMF was defined as: (1) the development of hematologic
toxicity (WHO grades 3 or 4) (Table 1) associated with no
recovery after 6 weeks or (2) death due to BMF after the last
223
Ra cycle.
223
Ra treatment
223
Ra treatment was performed in 110 mCRPC patients. All
patients had bone metastases; additionally, 36 % of these patients had visceral and/or nodal metastases. All patients completed between one and sicx cycles of 223Ra.
Eligibility criteria for treatment with 223Ra consisted of
being older than 18 years and signing the informed consent.
In addition, it was necessary to have ANC>1.5 K/μl and
PLT>100 K/uμl Hb levels below 10 g/dl were not an exclusion criterion and patients with lower Hb levels were transfused prior to 223Ra. Intravenous infusions of 50 kBq/kg
(1.4 μCi/kg) of 223RaCl2 doses were injected every 4 weeks.
Prior to next the 223Ra cycle, ANC had to be above 1.0 K/μl
and PLT>50 K/μl. After each 223Ra cycle, the patients were
counseled regarding expected side effects and precautions of
the radiopharmaceutical.
Statistical methods
Patient and clinical characteristics were summarized using
descriptive statistics. Associations between 223Ra cycles over
time and pain scores as well as ALP levels were evaluated
using repeated measures analysis of variance with an unstructured covariance matrix.
Survival times were estimated using the Kaplan-Meier
method. Associations between OS, PFS, TTP, BeFS and
BMF and clinical measures of interest were determined using
univariable and multivariable Cox proportional hazards regression models. Treatments received (chemotherapy, EBRT,
and secondary hormonal therapy) and measures obtained
(ECOG status and PSADT over 223Ra treatment) after the start
time of each survival outcome were included in the Cox
models as time-dependent covariates. The PSADT was computed in two ways: (1) for each consecutive PSA value and (2)
for the first and last PSA values. Of note, the start date for all
survival outcomes in the assessment for PSADT from initial to
final value was the last 223Ra cycle date. The following formula [6] was used to compute PSADT:
½logð2Þ ðtime interval between PSA valuesÞ
½logðfinal PSAÞ−logðinitial PSAÞ
All statistical analyses were performed using SAS 9.3 for
Windows (© 2011 by SAS Institute Inc., Cary, NC, USA). All
statistical tests used a significance level of 5 %. No adjustments for multiple testing were made.
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Results
The median age of the mCRPC patients prior to their first
223
Ra cycle was 69.0 years (42.4–88.1 years); the median
follow-up time was 8.3 months (0.4–18.4 months).
223
Ra cycles and time-to-event outcome measures
A total of 532 223Ra doses were delivered to 110 patients. The
details on patient characteristics are described in Table 2.
223
Ra cycles ranged from 1 to 6 (mean=5). These cycles were
completed in 58 (53 %) patients, while 4 patients (4 %) were
still undergoing 223Ra treatment at the time of analysis. The
planned course of six infusions of 223Ra was interrupted in 48
patients (44 %) due to progression and one or more of the
following: hematologic toxicity (n=22), declining ECOG status by two points (n=20), or a skeletal-related event (n=11).
The median [95 % confidence interval (CI)] OS time was
11.7 (8.6–15.7) months, PFS was 4.3 (3.0–5.5) months, TTP
was 4.4 (3.0–5.5) months, BeFS was 8.6 (6.9–11.9) months,
11
and BMF was 5.8 (3.3–8.6) months (Fig. 1). Among the 110
patients studied, 50 (45 %) died, 85 progressed (77 %), and 24
(22 %) suffered a skeletal-related event. Only 92 of the 110
patients had a sufficiently long enough follow-up time to evaluate BMF and among these, 32 (35 %) developed BMF.
A significant association between RaTot and OS, PFS,
BeFS, and BMF was observed for the mCRPC patients in this
study (Table 3), independently and when adjusting for other
measures (multivariable analysis). An increase in the number
of 223Ra cycles reduced the risk of each outcome. In addition,
more 223Ra cycles delivered were significantly associated
with a reduction in pain scores (p=0.041) (Fig. 2) and ALP
levels (p<0.0001) (Fig. 3).
Tolerability of 223Ra
Prior to their first 223Ra cycle, 13 patients had Hb levels below
10.0 g/dl (6.6–9.8 g/dl). None of these patients received
erythropoietin-stimulating agents 4 weeks prior to 223Ra.
The evaluation of hematologic toxicity was possible in 92
Table 2 Clinical characteristics
of 110 patients submitted to 223Ra
therapy
Primary tumor stage—at initial diagnosis of prostate cancer
Gleason score—at initial diagnosis of prostate cancer
Final stage—at initial diagnosis of prostate cancer
Initial ECOG status prior to 1st 223Ra cycle
Initial pain score prior to 1st 223Ra cycle
Hb levels prior to 1st 223Ra cycle (Hbinitial)
PSA levels prior to 1st 223Ra cycle (PSAinitial)
ALP levels prior to 1st 223Ra cycle (ALPinitial)
UNKN unknown/missing data
n
%
T2a
T3a
T4
27
49
3
25
45
3
UNKN
4–7
8–10
UNKN
II
31
30
72
8
21
28
27
65
7
19
III
IV
38
49
35
45
UNKN
0
1
2
3
0
1
2
3
Hb<10
Hb≥10
PSA≤10
PSA>10
UNKN
ALP<146
ALP≥146
UNKN
2
35
46
22
7
33
34
33
10
16
94
26
82
2
64
43
3
2
32
42
20
6
30
31
30
9
15
85
24
75
2
58
39
3
12
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Fig. 1 Outcome measures after 223Ra in 110 patients. a Overall survival. b Progression-free survival. c Bone event-free survival. d Bone marrow failure
patients. The mean and median times to nadir were 3.3 weeks,
with a maximum of 6.5 weeks.
During 223Ra, hematologic toxicity was grade 3 in 1.9 % of
patients and 0 % had grade 4 toxicity. However, after 223Ra,
BMF occurred in 32/92 patients (11 due to grade 4 toxicity
and 18 due to grade 3 toxicity). Grade 4 thrombocytopenia
occurred in ten patients (11 %) and grade 3 thrombocytopenia
in ten patients (11 %). BMF was clinically attributed to disease
progression in nine (10 %) patients that developed G3/G4
anemia with only G1/G2 thrombocytopenia. BMF was clinically attributed to 223Ra in four (4 %) patients that had G3/G4
thrombocytopenia with only G1/2 anemia. Finally, BMF may
have been induced by 223Ra in an additional 16 patients
(17 %) that developed G3/G4 anemia associated with G3/G4
thrombocytopenia.
Of the 32 patients who developed BMF, 5 received concurrent chemotherapy during their 223Ra cycles, including cyclophosphamide (n=6), cabazitaxel (n=1), mitoxantrone (n=1),
and paclitaxel (n=1). However, there was no statistically significant increased risk of BMF in patients treated with concomitant 223Ra and chemotherapy compared to like those
treated with 223Ra alone (p=0.71).
Of the patients who developed BMF, three patients had
EBRT concurrent to 223Ra and two had EBRT after 223Ra;
the association between BMF development and the use of
EBRT was significant (p=0.009) and an independent predictor (p=0.013) (Table 4).
The development of BMF in relation to 223Ra therapy was
in itself a predictor of survival. The median OS for the 60
patients who did not develop BMF was not reached [18 of
the 60 (30 %) died], while the median OS (95 % CI) for the 32
patients that did develop BMF was 6.97 months (5.68–8.21),
where 28 of the 32 (88 %) patients died.
Clinical and laboratory parameters and time-to-event
outcome measures
Based on imaging, 55 (50 %) patients were categorized as
having high skeletal tumor burden, 35 (32 %) intermediate
skeletal tumor burden, and 20 (18 %) low skeletal tumor
burden. Nodal metastases at baseline were noted in 26
(24 %) patients and were located in the abdomen and pelvis
in 19 patients and in the thorax and abdomen/pelvis in 7
patients. Visceral metastases at baseline were present in 13
(12 %) patients and these lesions were located in the brain
(n=1), liver (n=7), and lungs (n=5). In all cases, visceral
metastases were previously treated and felt to be quiescent.
In addition, four patients had prior history of secondary
cancer (one follicular lymphoma, one renal cell carcinoma,
and two bladder cancers).
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Table 3 Univariable and
multivariable models of OS and
PFS in relation to clinical and
laboratory parameters
13
Variables
OS
HR
PFS
p value
95 % CI
HR
p value
95 % CI
Univariable analysis
Total number of 223Ra cycles
0.51
Hb levels prior to 223Ra
0.42–0.62
1.72
<10 g/dl vs ≥10 g/dl
PSA levels prior to 223Ra
0.83–3.55
1.23
>10 ng/ml vs≤10 ng/ml
ALP levels prior to 223Ra
0.60–2.54
2.52
≥146 UI/L vs <146 UI/L
PSADT
1.42–4.46
1.02
1st and last
ECOG status prior to 223Ra
0.97–1.06
1.51
Pain score prior to 223Ra
1.11–2.04
1.67
Chemotherapy prior to 223Ra
1.25–2.24
0.92
Yes vs no
EBRT prior to 223Ra
0.52–1.61
1.26
Yes vs no
Abiraterone during/after 223Ra
0.61–2.61
0.23
Yes vs no
Multivariable analysis
0.09–0.58
Total number of 223Ra cycles
0.56
PSA levels prior to 223Ra
0.45–0.69
N/I
<0.0001
0.63
<0.0001
0.14
0.54–0.72
1.54
0.15
0.57
0.85–2.78
2.12
0.011
0.002
1.19–3.76
2.02
0.002
0.49
1.31–3.12
1.00
0.85
0.008
0.97–1.03
1.42
0.003
0.001
1.12–1.79
1.51
<0.001
0.76
1.20–1.89
1.07
0.76
0.53
0.70–1.63
1.01
0.99
0.002
0.57–1.78
0.32
<0.0001
0.18–0.55
<0.0001
0.67
<0.0001
N/I
0.58–0.78
1.48
0.22
0.51
>10 ng/ml vs≤10 ng/ml
ALP levels prior to 223Ra
0.95
0.88
0.80–2.74
1.19
≥146 UI/l vs <146 UI/l
ECOG status prior to 223Ra
0.49–1.86
1.42
0.13
0.72–1.964
1.16
0.44
Pain score prior to 223Ra
0.91–2.21
1.33
0.20
0.80–1.68
1.23
0.31
Abiraterone during/after 223Ra
0.86–2.05
0.32
0.035
0.83–1.82
0.53
0.044
Yes vs no
0.11–0.91
0.28–0.98
Bold citations refer to significant levels of p-values (p<0.05)
HR hazard ratio, N/I not included
Tables 3 and 4 describe the outcome measures in relation to
the clinical and laboratory parameters. Pain score above 2
prior to 223Ra was significantly associated with a higher risk
of death, progression, skeletal-related events, and development of BMF (p≤0.001). Baseline severe skeletal pain was
the only variable that remained significantly associated with
increased risk of a skeletal-related events, when controlling
for other measures (multivariable analysis) (p=0.042).
A decline in ECOG status prior to 223Ra significantly increased the risk of death, progression, of a skeletal-related
event, and of developing BMF (p≤0.008). Moreover, there
was a threefold increase in the risk of progression after
223
Ra treatment with an ECOG>2 [hazard ratio (HR)=3.79;
95 % CI 2.39–5.99; p value<0.0001] (Fig. 4). However, on
multivariable analysis the ECOG status was not significantly
associated with any of the outcome measures.
ALP≥146 UI/l prior to beginning the 223Ra cycles was significantly (p≤0.010) associated with a higher risk of death, progression, skeletal-related events, and developing BMF. When
considering other measures (multivariable analysis) ALP≥146
UI/l was not associated with any of the outcome measures.
An initial PSA>10 ng/ml doubled the risk of progression
(p=0.011) but this significant association was not maintained
with multivariate analysis. Additionally, the PSADT from first
14
Fig. 2 Trend in pain score from the 1st to the 6th 223Ra cycles. There is a
slight increase in pain between the 1st and 2nd cycles (flare phenomenon)
and subsequently the pain improves when the patients receive the 3rd,
4th, and 5th 223Ra cycles
223
Ra cycle to last 223Ra cycle was not associated with OS,
PFS, BMF, and BeFS. On the other hand, PSADT calculated at
two consecutive 223Ra cycles was significantly associated
with OS, PFS, TTP, and BeFS. PSADT of less than 3 months
increased the risk of each outcome by at least fivefold compared with PSADT ≥3 months (p≤0.006) (Fig. 5).
A baseline Hb level below 10 g/dl was associated with a
fourfold increase in the risk of developing BMF (p<0.001)
although this association did not persist when adjusted for
other measures (multivariable analysis).
Treatments performed prior to, during, and after 223Ra
cycles
Tables 3 and 4 describe the outcome measures in relation to the
treatment regimens, and Table 5 describes the types of treatments performed prior to, during, and after 223Ra. All patients
Eur J Nucl Med Mol Imaging (2016) 43:8–20
were receiving prednisolone, bisphosphonates, and luteinizing
hormone-releasing hormone (LHRH) analogue therapy.
Prior to 223Ra cycles, 55 patients had received secondary
hormone therapy, 56 patients had undergone chemotherapy,
and 16 patients were treated with EBRT. The median time to
initiate a secondary hormone therapy prior to the first 223Ra
cycle was 9.3 weeks (0–36.3 weeks), while the median time to
end chemotherapy prior to the first 223Ra cycle was 6.7 weeks
(0–165.7 weeks). There was no significant difference in OS,
PFS, or BeFS between patients receiving or not receiving
chemotherapy prior to 223Ra, nor was there a difference in
the risk of developing BMF.
The median time between completion of EBRT and initiation of 223Ra was 9.2 weeks (1.9–70.1 weeks). The use of
EBRT prior to 223Ra was not associated with any improvement in OS, PFS, or BeFs and was not associated with increased risk of BMF.
At the end of 223Ra therapy, 49 patients either began or
continued a secondary hormone therapy regimen, with a median time to begin treatment of 13.9 weeks from the first 223Ra
cycle. There was a significant benefit in the use of abiraterone
concomitant to 223 Ra in terms of OS, PFS, and BeFs
(univariable: p<0.002 and multivariable: p<0.044). The use
of abiraterone with 223Ra reduced the risk of death and of a
skeletal-related event by 77 % and the risk of progression by
68 %. On the other hand, the use of enzalutamide concomitant
to 223Ra did not improve outcome in these patients.
Chemotherapy was administered to 13 (12 %) patients during 223Ra treatments and to 27 (25 %) patients after completion of 223Ra treatments. The median time to begin chemotherapy after initiation of the first 223Ra cycle was 15.1 weeks
(0–57.3 weeks). EBRT was performed concurrently with
223
Ra in 13 (12 %) patients, with a median time to begin
EBRT of 16.4 weeks (0.1–29.3 weeks).
Discussion
223
Fig. 3 Trend in ALP levels from the 1st to the 6th 223Ra cycles. There is
steady decline in ALP levels throughout the 223Ra cycles
Ra dichloride is approved for clinical use in patients with
CRPC and symptomatic skeletal metastases based on an improvement in OS compared to patients receiving placebo [2].
However, experience suggests that not all patients receive the
same level of benefit from 223Ra. One challenge has been to
identify factors that may predict response to radium and to
identify patients in whom radium may not control their disease. Additionally, there is debate over the timing of radium
administration in the course of disease, whether to administer
early on or to delay until other options have been exhausted.
In this study, we reviewed our extensive clinical experience
with 223Ra in patients with prostate carcinoma. These patients
represented a broad spectrum of demographics, including age,
disease burden, laboratory values, and prior and concurrent
therapies. We retrospectively assessed these clinical
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Table 4 Univariable and
multivariable models of BMF and
BeFS in relation to clinical and
laboratory parameters
Variables
15
BMF
HR
BeEFS
p value
95 % CI
HR
p value
95 % CI
Univariable analysis
Total number of 223Ra cycles
0.70
Hb levels prior to 223Ra
0.56–0.87
4.71
<10 g/dl vs ≥10 g/dl
PSA levels prior to 223Ra
2.18–10.20
0.94
>10 ng/ml vs≤10 ng/ml
ALP levels prior to 223Ra
0.38–2.30
3.97
≥146 UI/l vs <146 UI/l
PSADT
1.87–8.45
1.01
1st and last
ECOG status prior to 223Ra
0.96–1.06
1.90
Pain score prior to 223Ra
1.29–2.82
2.00
Chemotherapy prior to 223Ra
1.36–2.93
1.14
Yes vs no
EBRT prior to 223Ra
0.56– 2.33
1.44
Yes vs no
Abiraterone during/after 223Ra
0.59–3.52
N/E
Yes vs no
EBRT during or after 223Ra
Yes vs no
Multivariable analysis
Total number of 223Ra cycles
4.30
0.001
0.58
<0.0001
<0.001
0.49–0.69
1.43
0.31
0.89
0.72–2.83
1.08
0.81
<0.001
0.57–2.04
1.97
0.010
0.82
1.18–3.30
1.02
0.21
0.001
0.99–1.06
1.77
<0.0001
<0.001
1.33–2.37
1.96
<0.0001
0.71
1.48–2.60
0.98
0.95
0.42
0.59–1.63
1.34
0.39
N/E
0.69–2.57
0.22
<0.001
0.009
0.09–0.51
9.99
<0.0001
1.44–12.84
0.027
0.62
<0.0001
Hb levels prior to 223Ra
0.57–0.97
1.52
0.39
0.52–0.75
N/I
N/I
<10 g/dl vs ≥10 g/dl
ALP levels prior to 223Ra
0.58–3.97
2.64
0.07
0.62
0.15
≥146 UI/l vs <146 UI/l
ECOG status prior to 223Ra
0.92, 7.59
1.57
0.10
0.32–1.19
1.28
0.24
Pain score prior to 223Ra
0.92–2.70
1.02
0.96
0.85–1.92
1.56
0.042
Abiraterone during/after 223Ra
0.53–1.97
N/E
N/E
1.02–2.39
0.33
0.020
0.013
0.31–0.84
N/I
N/I
Yes vs no
EBRT during or after 223Ra
Yes vs no
0.75
4.88–20.46
4.38
1.37–14.03
Bold citations refer to significant p-values (p<0.05)
BMF bone marrow failure, BeFS bone event-free survival, HR hazard ratio, Hb hemoglobin, EBRT external beam
radiation therapy, N/E not estimated, N/I not included
parameters for their association with outcome measures including OS, PFS, BeFS, and development of BMF.
Overall, we found that 223Ra had a clear benefit in the
treatment of mCRPC patients. There was a significant correlation between the number of radium doses delivered and
better outcome. Patients who completed the planned sixcycle 223Ra therapy had a reduced risk of death (−44 %),
progression (−33 %), skeletal-related event (−38 %), and
development of BMF (−30 %) compared to patients who did
not receive all six doses. We conducted a subgroup analysis of
patients that did not complete all six cycles of 223Ra due to
progression and were switched to chemotherapy with those
patients that, despite progression, completed all six cycles of
223
Ra. The median OS of the second group (15.7 months) was
significantly longer than the first group (7.2 months;
p < 0.0001). Even after excluding those patients who
16
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Table 5
Treatment regimens prior to and during/after 223Ra
Before
223
Ra
223
Total, n (%)
Cyclophosphamide
56 (51)
5
40 (36)
20
Docetaxel (Taxotere®)
8
5
Cabazitaxel (Jevtana®)
31
5
5
3
1
1
0
0
C-met inhibitor
Cisplatin
Topotecanc
1
1
1
1
2b
0
Crizotinib
Doxorubicin (Adriamycin®)
1
1
0
1
Carboplatin (Paraplatin®)
Mitoxantrone (Novantrone®)
Selinexor (KPT-330)
Secondary hormone therapy
Total, n (%)
0
0
0
1
1
1
55 (50)
49 (45)
Abiraterone
Enzalutamide
Diethylstilbestrol
EBRT
38
16
1
31
14
4
16 (15)
13 (12)
Types of treatments prior to, during,
or after 223Ra
During/after
Ra
Chemotherapy
a
Paclitaxel (Taxol®)
RAD001 (Everolimus®)
Dovitinib (TKI-258)
Fig. 4 Trend in ECOG score from the 1st to the 6th 223Ra cycles.
Although there is not a significant overall change in the patient’s ECOG
status throughout the 223Ra therapy, a slight increase in ECOG score
occurred at the 3rd 223Ra cycle at which time the patients progressed.
Afterwards, the ECOG score decreases (patient status improved)
discontinued the 223Ra cycles because of unrecoverable hematologic toxicity, 223Ra was still beneficial (OS: HR=0.44;
95 % CI 0.33–0.59; p < 0.0001). Notably, patients who
discontinued 223Ra because of progression (either skeletal or
extraskeletal) and were switched to another therapy had worse
outcomes compared to patients who continued with 223Ra
despite progression.
Although our patients had a median OS time of 12 months,
shorter than the phase III placebo-controlled trial [2] (median
OS=14 months), our patient population is somewhat different
from that in the trial. At initial diagnosis, prior to the first
223
Ra cycle, 82 % of our patients had skeletal tumor burden
Fig. 5 Trend in PSADT (in months) from the 1st to the 6th 223Ra cycles.
Between the 1st and 2nd 223Ra cycles, the mean PSADT is 3.78 months.
Throughout therapy, as the patients present signs of disease progression at
the 3rd 223Ra cycle, it is clearly noted that the PSADT rate increases
(mean=2.2 months from the 2nd to 3rd dose and mean=0.55 months
from the 3rd to 4th dose). Afterwards, the PSADT rate reduces (mean=
2.35 months between the 4th and 5th dose)
Total, n (%)
a
With or without carboplatin
b
In one patient cisplatin was combined with etoposide (VP-16)
c
Intraventricular administration
classified as high or intermediate. Additionally, 12 % had
visceral metastases and 24 % had nodal metastases. Even despite these factors, we confirm a benefit to 223Ra therapy in
these patients with more advanced disease (Table 6).
Similar to other reports that have identified skeletal parameters as prognostic markers of survival in mCRPC patients [4],
we found that the presence of bone pain, ALP≥146 UI/l, and a
poor ECOG status were predictive of OS, PFS, BeFS, and
BMF. In addition, the presence of bone pain independently
predicted the risk of a skeletal-related event in these patients.
In the majority of the patients there was a significant reduction in pain and ALP levels and improvement in the ECOG
status throughout the 223Ra cycles (Fig. 6), as has been previously reported [7]. However, increased pain during 223Ra occurred in 14 % of the patients due to a flare phenomenon,
especially between the first and second cycles. Because of
the intensity of the flare phenomenon, 5 % of the patients
had to discontinue 223Ra or had to undergo EBRT to control
pain. Although the flare phenomenon has been described in
prior studies with 223Ra in CRPC patients, none have described the rate of discontinuation of 223Ra cycles due to the
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Table 6 Comparison of
characteristics of our patient
population vs ALSYMPCA trial
[2]
17
ALSYMPCA trial
Current study
70 (43–89)
Age (years)
Median (range)
71 (49–90)
Initial ECOG score (%)
0
27
32
1
≥2
60
13
42
26
Pain score (%)
0
1
30
1
2
42
25
31
30
3
32
9
Hb (g/dl)
PSA (ug/l)
Median (range)
Median (range)
12.2 (8.7–15.5)
211 (32–6,431)
11.6 (6.6–15.6)
37 (0.4–2,433)
ALP<220 U/l
Extent of disease
Median (range)
<6 metastases
146 (3.8–6,026)
16
124 (48–1,387)
0
6–20 metastases
43
18
>20 metastases
Superscan
32
9
32
50
intensity of the pain [8, 9]. The patients that developed a flare
response had a remarkable symptomatic improvement in the
subsequent cycles. Comparing those six patients with the rest
of the sample, there was no significant difference in OS, although patients with a flare response had shorter median OS
(median: flare=8.3 months, no flare=11.7 months; p=0.27).
Surprisingly, there was a clear OS and PFS benefit of the
concomitant use of 223Ra with abiraterone. In our population,
patients receiving abiraterone plus 223Ra had a 77 % reduction
in the risk of death, 88 % reduction in the risk of a skeletalrelated event, and a 68 % reduction in the risk of progression.
Phase III trials found a survival benefit of the abiraterone arm
when evaluating abiraterone vs placebo (14.8 vs 10.9 months)
and especially in patients progressing after docetaxel (15.8 vs
11.2 months) [10–12]. A synergistic interaction between
abiraterone and EBRT has been described [13], and the same
may hold true for the concomitant use of abiraterone and 223Ra.
Despite prior studies demonstrating a survival benefit of
treating mCRPC patients with enzalutamide [14], a recent
comparison of the phase II trials evaluating enzalutamide
and abiraterone found no significant difference in OS among
these two secondary hormone therapies [15]. In our patient
population, enzalutamide concomitant to 223Ra did not demonstrate a significant OS or PFS advantage.
One might argue that the comparative benefit of
abiraterone vs enzalutamide in our patient population may
be due to a difference in patient selection as patients that were
on abiraterone might have had a lower burden of disease than
those on enzalutamide. However, in our study, mCRPC patients with initial ECOG status 2 and 3 were more prevalent in
the abiraterone group than the enzalutamide group (14 vs 7 %,
respectively). Similarly, more mCRPC patients underwent
chemotherapy prior to 223Ra in the abiraterone group than in
the enzalutamide group (51 vs 46 %, respectively). Therefore,
patients that had abiraterone plus 223Ra had, in general, at least
a similar (if not higher) burden of disease.
223
Ra was well tolerated with minimal hematologic toxicity
during cycles, with only 2 % of patients experiencing grade 3
toxicity and none grade 4 toxicity. However, BMF occurred in
a significant number of patients (35 %), despite the fact that
223
Ra was beneficial even in patients with a high tumor burden
(as 80 % of our patients had extensive disease). BMF was
most likely induced by 223Ra in 4 % of the patients and may
have been induced by 223Ra in an additional 17 %. Interruptions of 223Ra due to hematologic toxicity occurred in 15 % of
our patient population. These results are higher than those
reported in the literature [16]. Anemia is a common outcome
in CRPC patients; however, abnormal platelet and white blood
cell counts are rare [17]. Consequently, thrombocytopenia was
clearly an effect of radiation as PLT have the highest turnover
and because none of the patients were submitted to chemotherapy regimens (such as carboplatin) that cause major
thrombocytopenia. Although Hb<10 g/dl has been described
as predictive of BMF, among the 20 patients that developed
thrombocytopenia only 2 had prior anemia (both levels were
9.8 g/dl), while among the 9 patients with BMF due to anemia
(without thrombocytopenia) 5 had initial Hb levels below
10 g/dl, 3 of them with very low values (6.6, 7.5, and 8.1 g/
dl). There was no association between the use of chemotherapy and the development of BMF. On the other hand, there
was a significant association between developing BMF with
the concomitant use of 223Ra and EBRT. None of the clinical
and laboratory parameters were independent predictors of the
risk of developing BMF. To that effect, imaging biomarkers
with 18F-fluoride PET/CT may be useful to predict this outcome [18].
18
Fig. 6 Example of a good response to 223Ra cycles in an 84-year-old
patient diagnosed 3 years ago with a stage IV mCRPC (Gleason 9 and
bone metastases). Despite secondary hormonal therapy and narcotic pain
medication, he was losing weight, his pain was increasing, ECOG status
was declining, and the patient’s PSA and ALP levels were steadily rising.
a The whole-body 18F-fluoride PET/CT prior to the first 223Ra cycle
demonstrated multiple osteoblastic bone metastases, especially in the
lumbar spine and pelvis. After the 1st 223Ra cycle and prior to the 2nd
cycle, although the patient had a flare response, he gained weight.
Eur J Nucl Med Mol Imaging (2016) 43:8–20
Between the 2nd and 3rd cycles, his ECOG status improved (from 1 to
0). b The patient’s PSA levels declined from 8.4 ng/ml at the 1st 223Ra
cycle to 0.0 ng/ml after the 4th 223Ra cycle and was maintained at 0
thereafter. c The patient’s ALP levels declined from 268 IU/l at the 1st
223
Ra cycle to 70 IU/l after the 4th 223Ra cycle. d An interim whole-body
18
F-fluoride PET/CT scan (performed immediately prior to the 4th 223Ra
cycle) demonstrated marked improvement of the bone metastases, with
reduction of uptake
Eur J Nucl Med Mol Imaging (2016) 43:8–20
There are limitations to this study, as this was not a prospective randomized trial but rather an observational study based on
clinical experience. As such, the 110 patients we examined are a
heterogeneous group from actual clinical practice. The majority
had a high burden of disease, and not all patients completed the
full six cycles of 223Ra, either due to clinical intolerance or
medical decision to discontinue. Additionally, the concomitant
drug regimens were heterogeneous. When the patients
progressed during 223Ra, it was the oncologist’s decision to discontinue 223Ra and implement chemotherapy (or secondary hormone therapy) or to continue 233Ra with the addition of other
drugs (either chemotherapy or secondary hormone therapy).
Overall, the heterogeneity of the population provides a
broad perspective on the use of 223Ra in routine clinical practice and provides interesting observations and suggestions of
mechanisms and outcomes. In particular, the improved outcomes with continuation of 223Ra despite clinical or imaging
evidence of progression and with the concurrent use of 223Ra
and abiraterone are intriguing and bear further investigation in
a prospective trial.
19
Research funding This work is supported in part by the James E.
Anderson Distinguished Professorship Endowment, by the Cancer Center
Support Grant (NCI Grant P30 CA016672), and Fundação Amparo à
Pesquisa da Universidade de São Paulo (FAPESP 2014/03317-8).
Compliance with ethical standards
Authors’ disclosures of potential conflicts of interest All authors
declare that they have no conflict of interest. The authors declare no
financial (or other) conflict of interest relating to employment or leadership position, consultant or advisory, stock ownership, honoraria, expert
testimony, patents, royalties, licenses, or other remuneration.
Ethical approval This study was approved by the Institutional Review
Board (PA14-0848). Waivers of Informed consent and authorization were
granted for the retrospective analysis of the imaging data. All procedures
performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research
committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study formal
consent is not required.
References
Conclusion
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223
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some that had visceral and/or nodal metastases.
Our patients were able to tolerate chemotherapy and secondary hormonal therapy concomitant to 223Ra. Therefore, even in
patients with visceral metastases 223Ra can perhaps be considered alongside with chemotherapy, as there is a clear benefit in
terms of OS, PFS, and BeFS. For further definition of the safety
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needed. Additionally, patients who progress during 223Ra (developing visceral, nodal, or bone metastases) may benefit from
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Although BMF may occur after 223Ra, the median OS for
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