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Radionuclide Treatment in Metastasized Prostate Cancer
Henk G. van der Poel *
Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Article info
Abstract
Keywords:
Prostate cancer
Bone metastases
Radionuclide treatment
Painful osseous metastases are the major cause of cancer-related pain in
metastasized prostate cancer. In hormone refractory prostate cancer
multiple painful metastases can be treated with radionuclides. Initially,
Strontium-89 was successfully used for pain palliation with pain relief in
more than half the patients. More recently, radionuclides with shorter
physical half-lives such as Rhenium and Samarium were shown to result
in similar pain reduction rates, possibly lower myelosuppression incidences, and at least earlier recovery of hematological parameters allowing repetitive dosing. The low number of randomized trials on
radionuclides in prostate cancer does prohibit proper selection based
on efficacy and toxicity. Hence application is often dependent on local
availability of the different radionuclides.
# 2007 European Association of Urology and European Board of Urology.
Published by Elsevier B.V. All rights reserved.
* Tel. +31205122553; Fax: +31205122554.
E-mail address: [email protected].
1.
Introduction
The majority of patients with metastasized prostate
cancer experiences painful osseous metastases
during the course of the disease [1]. Androgen
ablation results in pain reduction in most patients
with painful metastases. In hormone refractory
prostate cancer (HRPC) painful osseous metastases
is one of the most prevalent clinical problems [2].
Local radiotherapy, chemotherapy, and bisphosphonates were shown to provide some pain relief [1].
Bone seeking intravenous radionuclide treatment is
an effective other modality in these patients.
Radionuclide treatment was initially introduced in
1942 using Strontium-89 (Sr89) [3].
Reported pain response rates to radionuclides
vary widely from 36% to 92% [4–7] probably
depending on assessment method and population
characteristics. Oosterhof et al. (2003) [7] showed
that patients with a smaller decrease in hemoglobin
concentration after radionuclide treatment had a
better pain response. Others found better responses
in patients with less extensive osseous involvement
[4,8–10].
Whether the relatively long half-life of 50.5 days
for Sr89 and toxicity of bone marrow suppression
account for the reported reduction in survival when
compared to external beam radiotherapy [7] is
unknown but it may favor the use of radionuclides
with shorter half-lives such as Rhenium-186 (Re186,
half-life 3.8 days), Re188 (17 hours), and Samarium153 (Sm153, 2 days) [11]. Although Re186 was shown
to be superior to placebo in a randomized trial [12],
only minimal differences with respect to efficacy
and toxicity of Re186 versus Sr89 was shown and
most non-randomized studies in breast and prostate
1871-2592/$ – see front matter # 2007 European Association of Urology and European Board of Urology. doi:10.1016/j.eeus.2007.02.002
Published by Elsevier B.V. All rights reserved.
114
eau-ebu update series 5 (2007) 113–125
cancer suggest similar efficacy for Sr89 and Re186
[5,8,13]. Whereas toxicity may be reduced in patients
treated with radionuclides with a shorter half-life,
such as Re186, and recovery from myelosuppression
may be shorter, Sr89 seems to provide somewhat
longer duration of efficacy. Sporadically, 117mSn
(low-energy conversion electrons) and 223Ra (alphaemitter) are used in bone metastases but experience
in prostate cancer management is limited [14,15].
The percentage of prostate cancer patients presenting with osseous metastases at initial diagnosis
decreased significantly over recent years. Moreover,
due to earlier diagnosis, many patients have HRPC
even before the clinical manifestation of osseous
metastases. This often implies that chemotherapeutic agents will be applied earlier in disease, in
some cases even in the absence of metastasized
disease. Although bisphosphonates seem to delay
skeletal related invents in the long run, they are less
effective in management of acute osseous pain. For
these reasons, radionuclide treatment may be value
in patients with osseous metastases from hormone
and chemotherapy refractory prostate cancer in
later phases of disease.
Here the most widely used radionuclides for
treatment of painful osseous metastases from
prostate cancer are reviewed.
Strontium-89 (Sr89) [18,19]. Both substances have a
natural tendency to bind to bone. Over 80% of the
total body phosphate is present in bone, bound as
inorganic phosphate to hydroxyapatite. Radiophosphorus, administered intravenously as P32-sodium
orthophosphate for skeletal targeting, was used
extensively in the 1970s to treat metastatic hormone
refractory prostate cancer (HRPC) [20]. More recent
data suggest equal efficacy after oral administration
[21]. The main disadvantage of P32 therapy is
dose-limiting myelosuppression with reversible
pancytopenia with nadir values at 5–6 weeks after
administration. In comparison to Sr89 the higher
myelotoxicity of P32 rendered Sr89 the radionuclide
of choice for painful osseous metastases [22]. P32 is
nowadays rarely used in the US or Europe but its
relatively low costs and oral availability make it a
potential alternative to Sr89.
Compared with hemi-body radiation the use of
radionuclides such as Sr89 provide pain relief from
multiple bone lesions with less toxicity like bowel
and pulmonary complaints often observed after
hemi-body radiotherapy. More recently used radionuclides such as Rhenium-186, Rhenium-188, and
Samarium-153 all lack the natural tendency to bind
bone. Hence, chelation with a bisphosphonate is
required to target these radionuclides to areas of
osteoclastic/osteoblastic activity (Table 1).
2.
History of radionuclide treatment for
osseous metastases
3.
Early studies using radionuclides for painful osseous
metastases comprise Phosphor-32 (P32) [16,17], and
Strontium is named after the UK-village it was first
discovered in in 1790. Strontium is close to calcium
Strontium-89 (Sr89)
Table 1 – Studies comparing pain response between different radionuclides
Radionuclides
N
Tumor
Study design
Sr89 vs Sm153
N = 57
Prostate
Sr89 vs 32P
N = 31
Various tumors
Non-randomized,
retrospective
Non-randomized
Sr89 vs Re186
vs Re188
Sr89 vs Re186
N = 44
Various tumors
Non-randomized
N = 50
Breast
Randomized
Sm153 vs Re186
N = 29
(prostate, N = 22)
N = 46
Various tumors
Non-randomized
Breast, Prostate
Non-randomized
N = 60
Prostate
Non-randomized,
retrospective (selection on
metastases extent)
Sm153-EDTMP
vs Re188-HEDP
Re186 vs Sr89
Result
No difference in pain response
rate and toxicity
No difference in pain response
rate and response duration.
Higher drop in platelet count
for P32 but not clinical relevance
No difference in pain response or toxicity.
Re188 best improvement in QoL
Earlier pain response in Re186,
similar duration of response,
earlier recovery from hematological
toxicity in Re186 (6w versus 12w)
Bone uptake and soft-tissue
clearance higher for Sm153
No differences in pain response,
Karnofsky performance score,
and bone marrow toxicity
No difference in response
rate or toxicity
Ref.
[49]
[21]
[13]
[5]
[91]
[11]
[35]
eau-ebu update series 5 (2007) 113–125
in the periodic table of elements and has the same
metabolic handling. Strontium-89 has a natural
affinity for metabolically active bone. The cause of
the higher affinity of Sr89 is debated. Since Sr89 is
close to calcium in the periodic table and bone
metabolism and turn-over is higher in osseous
metastases from prostate cancer it can be postulated that more readily uptake of calcium and Sr89 in
these areas accounts for the higher affinity
observed. Strontium-89 is a beta-emitter with a
physical half-life of 50.5 days. The partical range in
tissue is approximately 7 mm. Sr89 was shown to
have a higher affinity for tumor containing bone
than normal bone [23] and half-life in normal bone
(14 days) is considerably shorter than in tumor
containing bone (50 days). Excretion is renal and
thus glomerular filtration rate should be considered
prior to administration. A double-blind randomized
trial showed higher efficacy for Sr89 compared to
the Sr86 and Sr88 radionuclides [24]. The role of
dosing Sr89 is less clear. Dose-finding studies did not
find an association between pain relief and dose
[19,25]. Retrospective analyses, however, suggested
that higher doses of Sr89 resulted in improved pain
relief [26]. In general, 130–200 MBq is used to treat
osseous metastases in prostate cancer.
3.1.
Sr89 and pain response
A placebo-controlled randomized study using the
low dose of 75 MBq i.v. Sr89 could not confirm an
improvement in pain response superior to placebo
[27] whereas a higher dose of Sr89 (150 MBq) was
associated with a risk reduction of pain relief of 0.32
[24]. Initial studies using intravenous Sr89 showed
efficacy for pain relief as high as 80%. Complete pain
response rates vary widely among studies and have
been reported in 8–77% of cases whereas a reduction
in pain was reported by 18–50% of patients treated
with Sr89 for an overall response rate varying from
33 to 82% [24,25,28–34]. A pain flare occurs in 15% of
patients within one week after infusion [26]. The
duration of response varies between 14 days and up
to 15 months with a median of around 60 days
[7,35,36]. The problematic assessment of pain
response and documentation of analgetics use
hamper comparison between studies and probably
explains the wide variation in reported pain
responses.
Although Sr89 is assumed to exert pain relief
through a reduction in growth of bone metastases,
serological PSA and alkaline phosphatase responses
have only been observed in a minority of patients
[35,36]. In 37% of patients Turner et al. [37] observed
a more than 50% reduction in serum PSA whereas
115
Oosterhof et al. (2003) [7] found biochemical
responses in 13% of patients. Others, however, did
not observe a noticeable response when Sr89 was
applied to treat painful osseous metastases in HRPC
[35,38].
An important medical condition in patients with
HRPC is the development of acute spinal cord
compression (SCC) resulting in lower body paralysis.
Signs of SCC are a contraindication for radionuclide
treatment. The possible flare up after radionuclide
treatment and the higher efficacy of local treatment
such as external radiotherapy and surgery make
latter 2 options first choice. In a retrospective
analysis Soerdjbalie et al. (2002) [39] found a reduced
incidence of SCC during follow-up in patients
treated with Sr89 but not in patients treated with
the biphosphonate olpadronate.
3.2.
Sr89 toxicity
The most frequently observed toxicities are associated with the bone marrow suppression associated with Sr89 use: a reduction in white-blood cell
count and thrombocyte count between 11–65% in
more than half the patients. Blood cell counts do
return to normal within 8 weeks and rarely cause
grade 3 or 4 toxicity when Sr89 is applied to patients
with normal hematological parameters. The influence of Sr89 on serum hemoglobin concentration
seems to be limited and did not exceed the reduction
in serum hemoglobin observed in patients treated
with external beam radiotherapy [7]. No difference
in hematological toxicity between external beam
radiotherapy and Sr89 was observed in a randomized trial [7]. The reduced survival of patients treated
with Sr89 compared with external beam radiotherapy observed in this recent EORTC trial
remained unexplained but placebo controlled randomized studies with Sr89 could not confirm an
unfavorable effect of Sr89 on overall survival [24,27].
Similarly, other radionuclides were not associated
with decreased survival [24,27,40].
3.3.
Sr89 response prediction
Several patient characteristics could predict a
favorable response to Sr89. A normal serum hemoglobin prior to treatment is associated with a higher
pain response rate [10,35]. Oosterhof et al. (2003) [7]
found that patients who had a response to treatment showed a lesser decrease in median hemoglobin level after 4 and 8 weeks than those who did
not respond to treatment. This finding applied to
both radionuclide and external beam radiotherapy.
Beer et al. (2004) found an association between
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eau-ebu update series 5 (2007) 113–125
anemia, response to androgen ablation and survival
in patients with metastasized prostate cancer even
after correcting for extent of disease [41]. They
suggested that anemia may lead to increased
intratumoral hypoxia rendering tumor cells more
resistant to therapeutic interventions such as
radiation [42]. Moreover, possible etiological factors
of anemia such as cytokines (IL6, IL8) are often
elevated in prostate cancer patients [43] and may
play a role in response to pain stimuli in these
patients as well [44]. Hence, the factors leading to
anemia may increase pain perception and decrease
sensitivity to radiation through hypoxia thus resulting in a decreased pain response.
Other predictors of a poor pain response were low
performance status, higher serum PSA, more extensive osseous metastases [7,8], and poor PSA
response [45]. These findings make clear that
efficacy of Sr89 increases when applied in earlier
phases of disease where the patient has a better
performance, and less extensive disease and pain.
Repeated doses of Sr89 were shown to result in
similar pain response rates when compared to initial
treatment efficacy rates [9,28,35]. Due to myelotoxicity it is generally advisable to repeat dosing at
intervals of at least 6 weeks.
3.4.
Comparison of Sr89 and external beam radiotherapy
External beam radiotherapy is an effective means of
treating pain of osseous metastases in prostate
cancer. Several studies compared the efficacy of
external beam radiotherapy and Sr89. Oosterhof
et al. (2003) [7] compared Sr89 (150 MBq) and local
field external beam radiotherapy in a randomized
fashion. Patients treated with Sr89 showed a 34.7%
pain response rate whereas external beam radiotherapy resulted in pain reduction in 33.3% of
patients. One third of the study population had only
one painful metastatic site. The authors concluded
that the higher costs associated with radionuclide
treatment favor external beam radiotherapy. In
comparison to hemi-body radiotherapy Sr89 treatment showed similar response rates with fewer new
active sites during follow up suggesting that a
preventive effect was present after Sr89 treatment
[46,47]. Adjuvant high-dose Sr89 (400 MBq) to external beam radiotherapy did result in a reduced
number of new sites but not in less pain in the
initial painful site [48]. This additive effect to
external beam radiotherapy, however, was not
confirmed for the normal Sr89 dose (150 MBq) [40].
Data suggests that a combination of external
beam radiotherapy and Sr89 was of limited value for
pain control (Table 2).
3.5.
Comparison of Sr89 with other radionuclides and
chemotherapy
Comparison of Sr89 in osteoblastic metastases with
other radionuclides such as 32P [21], Rhenium-186
[5,13,35], and Samarium153 [49] showed comparable
efficacy for pain control. Most studies, however,
were non-randomized. In one randomized study of
patients with osseous metastasized breast cancer
the hematological parameters returned quicker to
baseline after treatment with Re186 compared to
Sr89 [5]. Hence, radionuclides based on Samarium
and Rhenium with shorter half-lives compared to
Sr89 may be preferable over Sr89 especially when
repetitive or chemotherapy-combined approaches
are considered.
In a recent report Nilsson et al. (2005) [50] used a
double-blind randomized study-design to compare
the palliative efficacy of a combination chemotherapy protocol (FEM, 5-FU, epirubicin, mitomycin-C)
and Sr89. Both arms in the study showed comparable reduction in pain score during the entire
12 weeks of the study. Treatment related toxicity,
however, was higher in the FEM arm where the
number of hospitalizations due to treatment toxicity
was twice as high as in the Sr89 arm.
4.
Rhenium-186 (Re186)
Rhenium is a group VII metal. Irradiation of enriched
Rhenium-185 produces the radionuclide Rhenium186 (Re186). Re186 decays with the emission of a beta
particle (Emax 1.07 Mev) and (9%) gamma ray
Table 2 – Comparison of radionuclides and external beam radiotherapy (EBRT = external beam radiotherapy,
Sr89 = Strontium-89)
n
Dearnaley et al. (1992) [47]
Quitly et al. (1994) [46]
Oosterhof et al. (2003) [7]
78
284
203
Study design
matched control
randomized
randomized
Radiotherapy
hemibody
hemibody/local
local
Pain reduction
Median survival
EBRT vs Sr89
EBRT vs Sr89
63% vs 52%
64% vs 66%
33% vs 35%
20w vs 21w
28w vs 33w
11m vs 7.2m
eau-ebu update series 5 (2007) 113–125
(137 keV) which renders it suitable for imaging
(Fig. 1) with a physical half-life of 3.8 days. Re-186
bound with the bisphosphonate hydroxyethylidene
diphosphonate (HEDP) was first described for treatment of painful bone metastases in the late 1970’s
[51,52]. The complexed Re186 binds to hydroxyapatite crystals by forming hydroxide bridges in a
hydrolysis reaction. Re186-HEDP is cleared from the
plasma with a half-life of 41 hours and the majority
is secreted within 24 hours with the urine. It has
been used for the palliation of bone pain in several
studies with response rates ranging from 30 to 80%
with mean duration of response of 7–9 weeks [53,54].
In a rat animal model, Re186-HEDP delayed clinical
symptoms from vertebral metastases such a leg
paralysis and urinary retention in the bladder [55].
The maximum tolerated dose for Re186-HEDP is
2960 MBq [56,57] and no dose response was noted in
the dose range of 1295–2960 MBq [58]. Typically, pain
response occurs 1–3 weeks after infusion with a
duration of 5–12 months. After approximately one
week a pain flare does occur in up to 50% of patients.
Toxicity has been shown to consist of thrombocytopenia whereas leucopenia seems to play a minor
role [59]. Grade 2 and 3 thrombocytopenia occurs in
117
12% and 7% respectively but rarely is clinically
relevant. The same applies for neutropenia that is
seen in 29% of cases but rarely results in clinical
interventions. In a randomized trial the Re186-HEDP
was shown to be superior over placebo: 27% of
patients reported pain relief compared to still 13% in
the placebo group [12]. Twenty of 131 men did not
receive Re186-HEDP due to rapid progression suggesting that the population in this study was in a
poor condition. Since a low serum hemoglobin and
poor performance were shown to be associated with
poor pain response [7,35] this may explain the
relatively low response rate compared to the 50% of
pain responses reported in other analyses [35,60].
At higher doses the use of Re186-HEDP is limited
by its myelosuppressive toxicity. Re186-HEDP at
higher doses (up to 5000 MBq) with autologous blood
stem cell rescue and re-infusion 2 weeks after Re186 injection was shown to result in a partial PSA
response in 20% of cases that received more than
3500 MBq [61]. No grade IV thrombocytopenia or
leucopenia was reported. These initial findings
resulted in a phase-II trial of 38 patients treated
with high dose Re186-HEDP (dose range 4770–
5100 MBq). In this second study 21% of patients
Fig. 1 – Comparison of Technetium-99 (Tc-99M) and Rhenium-186 (Re186) bone scan. Gamma-emitting radionuclides such
as Rhenium and Samarium can be used for imaging to confirm corrrect uptake of the therapeutic radionuclide to the areas
of bone activity found on the Technetium bone scan.
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eau-ebu update series 5 (2007) 113–125
experienced grade 3 thrombocytopenia with a nadir
platelet count value after 3 weeks. In 29% of cases a
PSA decrease of at least 50% was observed that
lasted for more than 4 weeks. The median duration
of PSA response was 5.6 months.
Re186-HEDP results in considerable pain relief
and mild toxicity at lower doses. At high dose,
Re186-HEDP resulted in a modest PSA response, but
significantly more bone marrow suppression.
5.
Rhenium-188 (Re188)
Another radionuclide derived from Rhenium is
Re188. Compared to Re186 it has a shorter half-life
(12 hours for the entire body and 16 hours in bone
metastases) [62]. In a dose-escalation analysis the
maximal tolerated dose was determined on 3.3 GBq
[63]. Pain palliation is reported in 66–77% of patients
with a complete response percentage of 16–25%
[6,11,64]. Moreover, an improvement in quality of
life-score was noted in the 6–12 week period
following Re188-HEDP infusion [6]. Similar to
Re186-HEDP, Re188 complexed to HEDP resulted in
hematological toxicity with a reduction in platelet
count in 20% of cases and a reduction in leucocyte
count in 25% of cases. These parameters return to
normal within 3 months and proper patient selection rarely results in serious toxicity [6,62,65,66]. An
alternative to Re188-HEDP is Re188 chelated to
dimercaptisuccinic acid (Re188-DMSA). Re188DMSA was shown to target bone metastases from
prostate cancer specifically but clinical experience is
limited to one report [67].
Palmedo et al. (2003) [68] studied the effects of
repetitive Re188-HEDP injections for pain palliation
in osseous metastases from prostate cancer. In a
randomized fashion patients were assigned to either
a single Re188-HEDP injection or 2 injections with an
8 week interval. Repetitive dosing not only improved
pain response but also resulted in a higher percentage of PSA responses (39% versus 7%) and significantly improved median overall survival from 7
months in the single dose group to 12.7 months in
the repetitive dosing group. Maximal toxicity in both
groups was transient grade-2 thrombocytopenia
and leukopenia.
A non-randomized comparison of Re188-HEDP
and Sm153-EDTMP in patients with painful metastases from prostate and breast cancer Liepe et al. [11]
showed comparable response and toxicity for both
agents.
Re188-HEDP was shown equally effective and
toxic to Sm153-EDTMP in non-randomized analyses
and repetitive dosing is feasible.
6.
Samarium-153 (Sm153)
Bombardment of enriched Samarium-152 with
neutrons in a nuclear reactor results in samarium153 (Sm153). Sm153 has no natural affinity for
bone but can be complexed with several aminocarboxylates and aminophosphonates such as ethylenediamine-tetramethylenephosphonate (EDTMP)
directing osseous targeting. Clearance from the
bloodstream is completed 6 hours after injection
and excretion is done in the urine [69] whereas
nuclear decay half-life is 1.9 days with 0.22 MeV
beta-emission and 103 keV gamma rays. Hence,
similar to Rhenium-based radionuclides Sm153EDTMP can be used for imaging. Bone metastases
bind 5 more Sm153 compared to normal bone [70].
Dose limiting toxicity consists of thrombocytopenia
and is seen in 20–42% of patients. In more than 95%
of patients platelet count normalizes within 5 weeks
[70–73]. Pain relief from osseous metastases after
Sm153-EDTMP occurs in 30–85% of patients in a
variety of tumors [74].
Several randomized, double-blind studies have
analyzed the efficacy of Sm153-EDTMP. A higher
dose (37 MBq/kg) was shown to be more effective for
palliation of pain from osseous metastases in both
breast and prostate cancer compared to a lower dose
(18.5 MBq/kg) [75]. In breast cancer patients, but not
in prostate cancer patients, the highest dose of
Sm153-EDTMP was associated with improved survival.
Another three-arm randomized trial comparing
low dose (18.5 MBq/kg) and high dose Sm153-EDTMP
(37 MBq/kg), versus placebo reported an improvement in pain for both low dose (42%) and high dose
(67%) Sm153-EDTMP after 4 weeks [76].
A more recent randomized phase-III trial compared Sm153-EDTMP to placebo [77]. Analgetics use
decreased significantly after a 2–4 week interval.
Moreover, 9% of patients in the Sm153-EDTMP group
showed a reduction of more than 50% in serum PSA
levels.
In all three trials only mild thrombocytopenia and
neutropenia were reported with platelet count
reduction between 43–55% and white-blood cell
count reduction between 45–60% at 3–4 weeks after
infusion. Normalization of hematological parameters was reported in all trials by 8 weeks.
Sm153 in repetitive dosing was shown to be
effective [70]. Repetitive dose was studied in 15
patients of which 13 (87%) showed pain improvement after secondary treatment. Both the median
duration of pain control (24 versus 8 weeks) and
survival (9 versus 4 months) in the retreated group
were substantially greater than for patients treated
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eau-ebu update series 5 (2007) 113–125
for example cisplatin and docetaxel are known and
exploited to increase efficacy of external beam
radiotherapy [78,79]. On the other hand, both
radionuclide and chemotherapy result in myelotoxicity and, therefore, hematological toxicity may
increase with the combination therapy. In the 2005
EAU-guidelines for prostate cancer [80] the authors
mention (section 16.10) that palliative treatment
with Samarium and Strontium radionuclides may
be effective but could compromise later chemotherapy due to myelotoxicity of both treatments. Recent
data, however, suggests that radionuclide treatment
does not prohibit further chemotherapy and that the
effects on bone marrow function is limited to the
first 6 to 12 months after administration [81].
with a single dose. However, 60% of the patients in
the re-treatment group required blood transfusions
for anemia. This increased efficacy of repeat dosing
was not observed in other studies [35]. Selection of
patients may have caused this inconsistency.
Repetitive dosing of Sm153 is feasible. When
treatment intervals exceed 6 weeks toxicity is
limited and reversible.
7.
Comparing radionuclides for efficacy
Based on effects of myelosuppression it can be
expected that radionuclides with shorter half-life
would potentially be less toxic. The local availability
and approval of use by regulatory bodies of radionuclides with shorter half-lives dictate the use in
different countries. So far, based on clinical efficacy
and toxicity data, none of these radionuclides has
shown convincing superiority of the others neither
with respect to efficacy nor with respect to toxicity.
Based on limited comparison analyses the shorter
half - life of Re188 compared to Re186 and Sm153 may
favor its use in the light of toxicity. The need for a
production facility close by the hospital with the use
of short half-life radionuclides such as Re188 may
prohibit the extensive use of the agents (Table 3).
8.
Combination therapy
8.1.
Radionuclides and chemotherapy
8.2.
Chemotherapy and Sr89
Sr89 was shown to be of benefit to patients that
earlier received and were resistant to chemotherapy
[36]. Conversely, Sr89 treatment did not prohibit
future chemotherapy application [81]. Akerley et al.
(2002) [82] showed that Sr89 (2.2 MBq/kg) in combination with estramustine (600 mg/m2) and vinblastine (4 mg/m2) resulted in a PSA decline of more than
50% for longer than 6 weeks in 48% of patients. Pain
response was not assessed in this non-randomizedstudy.
Pain response was improved upon the addition of
low-dose cisplatin (18 mg/m2) to Sr89 (148 MBq)
[83,84]. Any reduction in pain was experienced by
91% of patients in the combination arm against 63%
in the Sr89 monotherapy arm. However, the rate of
‘‘complete’’ response was not significantly different
for both arms. Interestingly, none of the hematological toxicity parameters was significantly different
for both arms. No significant difference in overall
Based on several findings there is reason to believe
that a combination of radionuclides and and
chemotherapeutic agents may have synergistic
antitumor activity. The radiosensitizing effects of
Table 3 – Available radionuclides for bone metastases targeting
Radionuclide
Bisphosphonate
T
Response
time
Response
duration
Energy
(MeV)
Particle type
32P
89Sr
153Sm-EDTMP
Phosphor
Strontium
Samarium
14.3 d
50.5 d
46.3 hrs
14d
21d
7d
10w
20w
8w
1.71
1.46
0.80
beta
beta
beta/gamma
186Re-HED
Rhenium
89 hrs
7d
8w
1.07
beta/gamma
188Re-HEDP
Rhenium
17 hrs
7d
8w
2.12
beta/gamma
117mSn-DTPA
Tin
13.6 d
14d
4w
0.13-gamma
gamma-photon
223Ra
Radium
–
–
Ethelenediaminetetramethylane
phosphoracid
Hydroxy ethylidene
difosfonaat
(etidronate)
Hydroxy ethylidene
difosfonaat
(etidronate)
Diethylene triamine
pentaacetic acid
–
11.4 d
–
–
28-alpha
alpa/gamma
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survival between Sr89 and S89+cisplatin was
observed.
The combination of Sr89 and doxorubicin after
two or three courses of induction doxorubicin was
found to prolong survival in a small randomized
trial. The addition of doxorubicin to Sr89 extended
median survival from 16.8 months in the doxorubicin only group to 27.7 months in the combined
treatment group [85].
These data suggest that a combination of Sr89 and
chemotherapeutic agents may potentially improve
survival in a subgroup of patients and has mild
toxicity. The limited data available prohibit widespread use of the combination, in particular with
respect to the effects on bone marrow suppression.
8.3.
Chemotherapy and Sm153-EDTMP
The ongoing TAXSAM study is a non-randomized
phase II analysis to evaluate the tolerability and
efficacy of a combination of Sm153-EDTMP and
docetaxel in patients with hormone refractory
prostate cancer. Docetaxel was administered at a
dose of 30 mg/m2 weekly for 5 weeks. Eighteen to
twenty-four hours prior to the fourth administration
of docetaxel, the approved dose of Sm153-EDTMP
(1 mCi/kg) was injected. Patients received a second
cycle of the TAXSAM combination regimen at PSA
and/or clinical progression. Grade 3 and 4 neutropenia was observed in 3 of 29 patients between
2–6 weeks after Sm153-EDTMP infusion. Thrombocytopenia higher than grade 2 did not occur. Within
12 weeks 34% and 18% of patients had a more than
50% reduction in serum PSA after the first and
second Sm153-EDTMP, respectively [86]. Higher PSA
response rates were reported by Fizazi et al. [87]
combining Sm153-EDTMP with docetaxel after a
positive response to 4 courses of 70 mg/m2 docetaxel
and estramustine 3-weekly. Twenty-five of 36 (69%)
of patients had a PSA decrease of more than 50% and
80% of patients reported a decrease in VAS-score
pain assessment by more than 2 points after the
initial 4 docetaxel induction cycles. Patients that
experienced a positive response after the initial
4 cycles of docetaxel were treated with a maintenance protocol with a single Sm153-EDTMP infusion combined with weekly docetaxel 20 mg/m2 for
6 weeks. For the patients that completed 6 weeks
maintenance treatment the pain response was 94%.
These data suggest that a single Sm153-EDTMP
treatment increases the incidence of grade 3–4
neutropenia of weekly docetaxel: 5% grade 3–4
neutropenia in docetaxel [88] compared to 10% in
the combination. Thrombocytopenia was not more
frequent in the combined treatment, whereas PSA
response and pain response were higher. Data from
ongoing randomized studies is needed here to
evaluate both pain response and survival of the
combination of chemotherapy and Sm153-EDTMP
treatment but initial findings seem promising.
8.4.
Bisphosphonates and radionuclide treatment
Bisphosphonate treatment was shown to result in a
modest reduction in pain from osseous metastases
in prostate cancer but pain relief occurred after
considerable longer intervals compared to radionuclide treatment [89]. Since bisphosphonates are
used to target Re186, Re188, and Sm153 to bone
metastases it was studied whether earlier treatment
with bisphosphonates may influence efficacy of
these radionuclides. Recently, a non-randomized
comparison in a small group of patients found that
the combination of zoledronic acid and Sr89 was
more effective for pain relief than either of the two
agents in monotherapy [90]. These limited findings
suggest that bisphosphonates not necessarily counteract the efficacy of radionuclide treatment and
patients experiencing pain while on bisphosphonates could continue these while receiving radionuclide treatment.
9.
Recommendations for radionuclide use
Data from both retrospective and prospective
studies do indicate that pain palliation obtained
by radionuclide treatment is most likely in patients
with relatively good performance status and pain
reduction can be obtained in over 50% of patients
which seems higher than for chemotherapy.
Pretreatment a bone scan be done to confirm
metastases and exclude patients with a so-called
super-scan, since it is generally assumed that bone
marrow toxicity may be higher in these patients.
Hematological parameters showed be assessed and
be higher than lower normal limits. It is recommended to use radionuclides only in patients with
renal clearance over 60 ml/min. As for chemotherapy, the likely of pain relief decreases when serum
hemoglobin starts to drop, this reflecting a poor
overall condition. Radionuclides with shorter physical half-lives, such as Sm153, Re186 and Re188,
that, based on the earlier recovery of bone marrow
toxicity compared to initially used radionuclides
(Sr89) could potentially be given at higher frequency
which favors repetitive use and supports treatment
earlier in the course of disease. Moreover, data
now clearly show that radionuclide treatment
not necessarily precludes further chemotherapy.
eau-ebu update series 5 (2007) 113–125
Considering the milder side-effect profile for radionuclides compared to chemotherapy it should be
considered first choice in patients with multiple
painful osseous metastases where external beam
radiotherapy is not feasible due to the number of
metastases. Moreover, radionuclide treatment
should be considered in patients with painful
metastases after chemotherapy. Combination of
radionuclide treatment and chemotherapy should
be considered experimental. Although increased
efficacy was has been observed for the combination,
the incidence of grade 3 and 4 neutropenia also
increased. A combination of bisphosphonates with
radionuclides was not associated with increased
toxicity and potentially increases efficacy of pain
relief.
121
- Bone marrow suppression with thrombocytopenia
and neutropenia occurs in similar frequency and
grade in all radionuclides but a shorter half-life
seems to be associated with earlier recovery to
baseline blood cell counts.
- Repetitive dosing of all radionuclides was shown
to be feasible when the intervals were at least
6 weeks.
- Combination of radionuclides with external beam
radiotherapy and chemotherapy was shown to be
beneficial, but toxicity increased significantly.
- Combination of radionuclides with chemotherapeutic agents should be considered an experimental treatment and study data are awaited.
References
10.
Future
Combination of chemotherapy and radionuclide
treatment and a direct comparison of both modalities should be studied. The initial findings of a
combination of Samarium based radionuclides and
docetaxel hold promise. Alpha-particle emitters
deliver a higher energetic and localized radiation
with a much smaller range in tissue than betaparticles. These alpha-particle radiation induces
predominantly non-reparable DNA double-strand
breaks which may kill dormant cells but alphaemitters are potentially more toxic and mutagenic
than beta-emitters. Further evaluation of alphaemitters such as Ra223 that has a natural affinity for
bone like Sr89 is awaited but initial data suggests
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11.
Remarks
- Pain response is seen in approximately half the
patients treated with radionuclides for painful
osseous metastases of prostate cancer.
- P32 and Sr89 show a natural affinity for bone,
whereas Re186, Re188, and Sm153 require chelation to bisphosphonates for targeting.
- Of the different radionuclides used those with a
shorter half-life such as Re186-HEDP, Re188-HEDP,
and Sm153-EDTMP showed similar efficacy compared to Sr89, with a longer half-life.
- Several parameters are associated with a favorable pain response: higher performance score and
lower pain score at treatment, higher serum
hemoglobin, and a limited number of osseous
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CME questions
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to answer these CME questions on-line. The CME
credits will then be attributed automatically.
1.
125
B. a-particles are potentially less toxic to cells
than b-particles.
C. a-particles cannot be used for the treatment of
prostate cancer.
D. a-particles result in DNA double-strand
breaks.
89
SrCl2 is a radionuclide for which one of the
following applies:
A. It does not have a natural ability to bind
bone.
B. Its physical half-life is <1 d.
C. Its efficacy for pain relief is markedly shorter
than other radionuclides.
D. It has a natural ability to bind bone.
2. Physical half-lives differ between radionuclides.
What is the correct order when ordered from
short to long physical half-life?
A. 89Sr; 186Re; 153Sm
B. 153Sm; 186Re; 89Sr
C. 186Re; 153Sm; 89Sr
D. 188Re; 89Sr; 153Sm
3. The a-emitting radionuclides are relatively new
in the field of palliation for bone pain from
metastases. Which of the following is true:
A. a-particles travel longer ranges in tissue
compared to b-particles.
4. The most prevalent typical toxicity of all radionuclides is:
A. Neuropathy
B. Hepatotoxicity
C. Nephrotoxicity
D. Thrombocytopenia
5. Which of the following radionuclides is not
dependent on a bisphosphonate for bone targeting?
A. 153Sm
B. 186Re
C. 188Re
D. 223Ra
6. Pain response to radionuclide treatment was
shown to be associated with:
A. Serum hemoglobin level
B. Patient age
C. Renal function
D. Location of bone metastases