Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide
Objective: Over the last decade, significant advances have been made in the development of therapies for patients with metastatic castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved overall survival compared to placebo. Rad...
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| Zitieren: | Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide / M.E. Jiménez Romero, S. Díez Farto, J.C. Navarro Serrato, E. Canelón Castillo, I. Revelo Cadena // Experimental Oncology. — 2018 — Т. 40, № 2. — С. 144–148. — Бібліогр.: 13 назв. — англ. |
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Jiménez Romero, M.E. Díez Farto, S. Navarro Serrato, J.C. Canelón Castillo, E. Revelo Cadena, I. 2019-01-24T09:57:18Z 2019-01-24T09:57:18Z 2018 Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide / M.E. Jiménez Romero, S. Díez Farto, J.C. Navarro Serrato, E. Canelón Castillo, I. Revelo Cadena // Experimental Oncology. — 2018 — Т. 40, № 2. — С. 144–148. — Бібліогр.: 13 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145592 Objective: Over the last decade, significant advances have been made in the development of therapies for patients with metastatic castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved overall survival compared to placebo. Radium-223 became the first approved radiopharmaceutical which decreased skeletal-related events, palliated pain, and showed improved overall survival in symptomatic patients with castration-resistant prostate cancer and bone metastasis only. Materials and Methods: We present the case of an eighty-two year old man with metastatic castration-resistant prostate cancer who was treated with sequential therapy (abiraterone — enzalutamide — radium-223). The sequencing and treatment used for our patient was viable because of his clinical characteristics, which have allowed for longer survival time with an acceptable quality of life. These actions must be agreed on by the Multidisciplinary Tumour Board, in order to optimize the use of available courses of treatment. Results: The treatment of these patients is changing rapidly, but many questions remain regarding the optimal sequencing of the available drugs. Sequential or concomitant use of the next generation hormonal agents — abiraterone and enzalutamide — cannot currently be recommended. Data regarding the safety of concomitant abiraterone, enzalutamide or denosumab with radium-223 is reassuring and timely. However, we cannot advocate the general use of combined radium-223 therapy at this time, irrespective of prior therapy. Conclusion: A better understanding of active mechanisms, the genetic characteristics of each metastatic castration-resistant prostate cancer and the development of new prognostic and predictive biomarkers will help determine sequencing or different combination treatments for each individual patient. Key Words: castration-resistant prostate cancer, treatment sequence, abiraterone acetate, enzalutamide, radiopharmaceutic. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Case report Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide Article published earlier |
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Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
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Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide Jiménez Romero, M.E. Díez Farto, S. Navarro Serrato, J.C. Canelón Castillo, E. Revelo Cadena, I. Case report |
| title_short |
Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
| title_full |
Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
| title_fullStr |
Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
| title_full_unstemmed |
Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
| title_sort |
clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide |
| author |
Jiménez Romero, M.E. Díez Farto, S. Navarro Serrato, J.C. Canelón Castillo, E. Revelo Cadena, I. |
| author_facet |
Jiménez Romero, M.E. Díez Farto, S. Navarro Serrato, J.C. Canelón Castillo, E. Revelo Cadena, I. |
| topic |
Case report |
| topic_facet |
Case report |
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2018 |
| language |
English |
| container_title |
Experimental Oncology |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Article |
| description |
Objective: Over the last decade, significant advances have been made in the development of therapies for patients with metastatic castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved overall survival compared to placebo. Radium-223 became the first approved radiopharmaceutical which decreased skeletal-related events, palliated pain, and showed improved overall survival in symptomatic patients with castration-resistant prostate cancer and bone metastasis only. Materials and Methods: We present the case of an eighty-two year old man with metastatic castration-resistant prostate cancer who was treated with sequential therapy (abiraterone — enzalutamide — radium-223). The sequencing and treatment used for our patient was viable because of his clinical characteristics, which have allowed for longer survival time with an acceptable quality of life. These actions must be agreed on by the Multidisciplinary Tumour Board, in order to optimize the use of available courses of treatment. Results: The treatment of these patients is changing rapidly, but many questions remain regarding the optimal sequencing of the available drugs. Sequential or concomitant use of the next generation hormonal agents — abiraterone and enzalutamide — cannot currently be recommended. Data regarding the safety of concomitant abiraterone, enzalutamide or denosumab with radium-223 is reassuring and timely. However, we cannot advocate the general use of combined radium-223 therapy at this time, irrespective of prior therapy. Conclusion: A better understanding of active mechanisms, the genetic characteristics of each metastatic castration-resistant prostate cancer and the development of new prognostic and predictive biomarkers will help determine sequencing or different combination treatments for each individual patient. Key Words: castration-resistant prostate cancer, treatment sequence, abiraterone acetate, enzalutamide, radiopharmaceutic.
|
| issn |
1812-9269 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/145592 |
| citation_txt |
Clinical case of a patient undergoing radium-223 treatment following treatment with abiraterone acetate and enzalutamide / M.E. Jiménez Romero, S. Díez Farto, J.C. Navarro Serrato, E. Canelón Castillo, I. Revelo Cadena // Experimental Oncology. — 2018 — Т. 40, № 2. — С. 144–148. — Бібліогр.: 13 назв. — англ. |
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144 Experimental Oncology 40, 144–148, 2018 (June)
CLINICAL CASE OF A PATIENT UNDERGOING
RADIUM-223 TREATMENT FOLLOWING TREATMENT
WITH ABIRATERONE ACETATE AND ENZALUTAMIDE
M.E. Jiménez Romero*, S. Díez Farto, J.C. Navarro Serrato, E. Canelón Castillo, I. Revelo Cadena
Urological Department of the University Hospital of Puerto Real, Cádiz 11510, Spain
Objective: Over the last decade, significant advances have been made in the development of therapies for patients with metastatic
castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved
overall survival compared to placebo. Radium-223 became the first approved radiopharmaceutical which decreased skeletal-related
events, palliated pain, and showed improved overall survival in symptomatic patients with castration-resistant prostate cancer
and bone metastasis only. Materials and Methods: We present the case of an eighty-two year old man with metastatic castration-
resistant prostate cancer who was treated with sequential therapy (abiraterone — enzalutamide — radium 223). The sequencing
and treatment used for our patient was viable because of his clinical characteristics, which have allowed for longer survival time with
an acceptable quality of life. These actions must be agreed on by the Multidisciplinary Tumour Board, in order to optimize the use
of available courses of treatment. Results: The treatment of these patients is changing rapidly, but many questions remain regarding
the optimal sequencing of the available drugs. Sequential or concomitant use of the next generation hormonal agents — abiraterone
and enzalutamide — cannot currently be recommended. Data regarding the safety of concomitant abiraterone, enzalutamide or de-
nosumab with radium-223 is reassuring and timely. However, we cannot advocate the general use of combined radium-223 therapy
at this time, irrespective of prior therapy. Conclusion: A better understanding of active mechanisms, the genetic characteristics
of each metastatic castration-resistant prostate cancer and the development of new prognostic and predictive biomarkers will help
determine sequencing or different combination treatments for each individual patient.
Key Words: castration-resistant prostate cancer, treatment sequence, abiraterone acetate, enzalutamide, radiopharmaceutic.
Prostate cancer (PC) is the second most com-
monly diagnosed cancer, and is the fifth leading cause
of cancer death in men [1]. Most of the men who are
diagnosed with PC present with apparent localized
disease. Despite initial treatment, some of these
men will go on to have disease progression, firstly
presenting with biochemical recurrence even if there
is no clinical or radiographic evidence of disease.
Then, many continue to progress and develop distant
metastatic disease. Other patients present with meta-
static disease de novo at the time of the first diagnosis.
Treatment for advanced disease usually begins with
androgen deprivation therapy. The majority of cases
initially respond to androgen-deprivation, progress-
ing towards castration-resistance. Most patients will
develop metastases — bone metastasis being the
most frequently observed — and an independent
poor prognostic factor [2]. Until recently, the only
treatment for these patients that had proven success-
ful in increasing overall survival rates was docetaxel.
In the last decade, significant progress has been made
in the development of new agents against metastatic
castration-resistant prostate cancer (mCRPC) [3].
Treatments based on abiraterone acetate (AA) [4]
and enzalutamide (ENZ) [5] were approved after the
publication of data which demonstrated an increase
of the overall survival rates, when compared to a pla-
cebo group, simultaneously reducing the time period
to the first skeletal-related event (SRE) and — in the
case of AA treatment — reducing pain. In the last
few years, the high efficiency and low toxicity of both
treatments, coupled with the experience acquired,
have changed the conditions of our patients suffering
from mCRPC. Furthermore, the therapeutic algorithm
of these patients has changed recently with the intro-
duction of radium-223, the first approved radiophar-
maceutical which has shown an improvement in pain
control, reduced SREs and increased survival rates
in symptomatic or minimally symptomatic patients with
mCRPC and bone metastasis.
MATERIALS AND METHODS
Eighty-two year old male with existing history
of high blood pressure, being treated with enalapril;
and of hypercholesterolemia, being treated with sim-
vastatin. Ex-smoker of 10 cigarettes a day for many
years. In August 2009, at 75 years of age, the patient
was diagnosed with a sigmoid colon adenocarcinoma
(stage IIA) requiring surgery (laparoscopic sigmoidec-
tomy) and adjuvant chemotherapy (since then, Onco-
logy has carried out several follow-up consultations
with no recurrence).
In May 2010, the patient attended our practice
following a referral from Oncology for a symptomato-
logy assessment of the lower urinary tract, present-
ing with high prostate-specific antigen (PSA) levels
(24.20 ng/ml). The rectal examination revealed a pros-
tate of increased size and mass. A transrectal prostate
biopsy was carried out, the results of which confirmed
a prostate adenocarcinoma with a Gleason score
of 8 (4 + 4, bilateral) with marked perineural invasion
Submitted: January 11, 2018.
*Correspondence: E-mail: miguelefrenjimenez@gmail.com
Abbreviations used: AA — abiraterone acetate; CT — computer-
ized tomography; ENZ — enzalutamide; mCRPC — metastatic
castration-resistant prostate cancer; PC — prostate cancer; PSA —
prostate-specific antigen; SRE — skeletal-related event.
Exp Oncol 2018
40, 2, 144–148
CASE REPORTS
Experimental Oncology 40, 144–148, 2018 (June)40, 144–148, 2018 (June) (June) 145
and extension to the prostate tissue on both lobes. The
extension study, carried out by means of computerized
tomography (CT), revealed an extracapsular exten-
sion, but no visceral or lymph node metastases. The
bone scan provided findings consistent with metastatic
bone disease (in the right sacroiliac region; clinical
stage cT3b N0 M1b).
Given these results and a PC diagnosis at an advanced
metastatic stage, continuous androgen- deprivation
therapy was initiated (six-monthly luteinizing-hor-
mone releasing-hormone agonist) + zoledronic acid
(4 mg administered intravenously on a monthly basis,
for 18 months) + calcium and vitamin D supplements.
Initially, monitoring took place at a follow-up visit three
months later and every six months after that.
A course of monotherapy with a six-monthly
agonist was initiated in July 2010, prompting a rapid
biochemical response and a reduction of PSA lev-
els, which reached their lowest point in December
2011 at 0.40 ng/ml. Testosterone remained at cas-
tration level. In March 2013, PSA levels increased
up to 2.78 ng/ml, which prompted further hormonal
treatment yielding a biochemical response lasting
up to August 2013 (PSA levels of 5.78 ng/ml). Conse-
quently, a new radiological assessment with a CT scan
was requested, which ruled out visceral metastases,
while the bone scan revealed new affected areas in the
left sacroiliac region and on the right ischium (Fig. 1).
Following the diagnosis of mCRPC, the patient was ex-
amined in a specific consultation which included a full
evaluation. The response to the 35-month androgen-
deprivation therapy presented a score of 0 according
to the ECOG scale; the patient was asymptomatic and
did not require analgesia (0, according to the brief
pain inventory — short form), although the patient did
complain of mild asthenia.
Fig. 1. Bone scan revealing affected areas in the left sacroiliac
region and right ischium
In light of all these considerations, treatment with
AA (four 250 mg capsules a day + 10 mg predni-
sone daily) was initiated in September 2013. At the
same time, it was decided that treatment for bone
metastasis be resumed by prescribing denosumab
(120 mg as a monthly subcutaneous injection). In June
2014, after 9 months of treatment, PSA levels reached
their lowest point, at 0.25 ng/ml, with alkaline phos-
phatase levels remaining within normal limits.
The patient remained stable, without clinical or ana-
lytical changes, no side effects, and with quarterly
check-ups (including a new CT scan and a bone scan
15 months after the beginning of treatment) until Au-
gust 2015. At that time, PSA levels, which had remained
stable thus far, increased to 8.30 ng/ml and alkaline
phosphatase levels increased to 154.5 U/l. A mild clini-
cal deterioration of the patient’s health was observed
and first-line analgesic treatment (paracetamol) was
prescribed with good results.
At the beginning of December 2015, after 27 months
of treatment, PSA levels were 30.43 ng/ml, with
significant asthenia and pain controlled by means
of the prescribed analgesic. Alkaline phosphatase
levels reached 342 U/l and a new extension study with
a CT scan and bone scan demonstrated advanced
bone metastasis (Fig. 2, 3).
Fig. 2. CT scan showing advancement of the bone metastasis
In February 2016, AA was suspended and it was
decided that treatment consisting of ENZ (four
40 mg capsules daily) be initiated. The patient pre-
sented with more acute asthenia and worsening hip
pain, which necessitated second-line analgesic treat-
ment (tramadol). Two months into the ENZ treatment,
and due to the limited clinical benefits observed —
associated with a reduced quality of life due mainly
to pain — this treatment was suspended and new ra-
diological tests were requested, with a view to starting
146 Experimental Oncology 40, 144–148, 2018 (June)
treatment based on radium-223. The CT scan of the
chest, abdomen and pelvis displayed advancement
of the bone meta stasis without visceral or lymph node
disease (Fig. 4). A basal haematological evaluation
was carried out including an absolute neutrophil and
platelet count, as well as an assessment of hepatic
and renal function, which did not contraindicate the
start of treatment. In this context of symptomatic
bone disease without visceral or lymph node dis-
orders, it was decided that treatment based on ra-
dium-223 be initiated.
Fig. 4. Chest, abdomen and pelvis CT scan; advanced bone
metastasis; lack of visceral or lymph node metastases
Close cooperation with the Nuclear Medicine Ser-
vice was established, and a joint follow-up schedule
was agreed upon, consisting of a full blood test before
each dose of radium-223. The patient completed six
full one-month cycles of treatment. He received the
first dose in May 2016, having previously suspended
treatment with calcium and vitamin D supplements.
Coinciding with the administration of the first dose, the
patient reported a slight increase of polyostotic bone
pain, corresponding to a flare effect described in the
pivotal study (ALSYMPCA) [6]. Four weeks later, fol-
lowing the administration of the second dose, the blood
tests detected an increase of PSA levels and a reduction
of alkaline phosphatase levels, showing pain relief and
good tolerance towards the treatment. Therefore, the
therapeutic programme was continued. Before the third
dose, the patient suffered from anaemia (Hb = 8.2 g/dl)
which prompted the decision to carry out two transfu-
sions of red blood cell concentrates. During the rest
of the dosage, the patient reported two isolated cases
of diarrhoea. Altogether, the patient showed very con-
siderable improvement in terms of pain relief and did not
require further analgesic treatment. Notwithstanding,
PSA levels increased up to 421 ng/ml, at the date of the
final dose, whereas alkaline phosphatase levels fell con-
siderably (187.7 U/l) without returning to normal levels.
In November 2016, a reassessment was carried
out after the course of treatment had been completed
which presented a mild clinical deterioration. The patient
continued to take a six-monthly agonist with a calcium
and vitamin D supplement, which was re- established
following the final dose of the radiopharmaceutical.
PSA levels remained stable (435 ng/ml) and alkaline
phosphatase levels increased up to 545 U/l.
At the end of December 2016, the bone and
CT scans displayed further progression of the bone
metastasis (Fig. 5). The patient was re-admitted twice
with anaemia, requiring a blood transfusion. At the
end of February 2017, they were admitted again for
anaemia, requiring a transfusion (Hb = 6.7 g/dl), and
predominantly evening asthenia with bone pain con-
trolled by means of a second-grade analgesic treatment
(tramadol). The monthly follow-up appointments were
continued (for the control of the anaemia and the pain).
Fig. 5. Diffuse bone metastasis on bone scintigraphy
Fig. 3. New bone scan showing advancement of the bone
metastasis
Experimental Oncology 40, 144–148, 2018 (June)40, 144–148, 2018 (June) (June) 147
Eighty-three months after the PC diagnosis and
as of March 2017, the patient has an acceptable quality
of life. Following completion of the treatment, we have
observed marrow toxicity and requested transfusions
every four to five weeks in order to treat grade 3 anae-
mia. The patient reports general bone pain which cur-
rently require third-line analgesic treatment (morphic
drugs). Considering all the above, it was decided that
systemic treatment with chemotherapy be ruled out.
DISCUSSION
The emergence of these new highly effective
therapies poses a significant clinical challenge;
in this regard, the current debate is trying to posi-
tion radium-223 within the therapeutic algorithm
of mCRPC [7]. The question is whether to administer
it before, during the course of the disease, concomi-
tant with new hormonal therapies or, on the contrary,
to wait until the patient progresses to a treatment with
chemotherapy, ENZ or AA. Furthermore, if the op-
tion chosen is to combine it with AA or ENZ, it would
be essential to know the efficacy and safety of this
combination.
Sequencing is being trialled with the hope of ob-
taining a cumulative benefit for survival. In the pre-che-
motherapy setting, the information currently available
is based on retrospective studies of very small series
and a highly heterogeneous patient population [8].
However, the efficacy of this practice has not been
backed up by data derived from clinical trials, and
evidence from potential cross-resistance reinforces
the debate surrounding the best sequence to use in or-
der to maximize the benefits. This situation becomes
more difficult given evidence showing the possibility
of administering hormonal agents in patients who
have not undergone chemotherapy and administering
new chemotherapeutic agents in patients sensitive
to hormone treatment. Thus, a thorough study is re-
quired, including the characteristics of each patient
and their disease, as well as safety profiles and the
efficiency of each drug, in order to be able to find
the best treatment sequencing for each individual,
whether as monotherapy or as in combination [9, 10].
For example, if a patient with an asymptomatic case
of mCRPC undergoing concomitant treatment with
docetaxel and radium-223 showed progression to the
bone, the possible options available later in terms
of bone pain treatment are drastically reduced. Defini-
tive data will be published soon regarding the safety
and efficiency of re-treatment with radium-223 in pa-
tients who have previously been administered with
docetaxel. These results may serve to clarify some
of our doubts.
In terms of a combination of treatments, Saad
et al. [11] have recently published a phase 3b trial ana-
lyzing the safety and efficiency of radium-223 and other
concomitant therapies in patients with CPRC. It includes
a total of 606 Caucasian symptomatic or asymptomatic
males, over 18 years old, with a prevalence of bone
disease and at least two bone metastases. Patients
with visceral disease were excluded but not those with
lymph node metastases. Patients were to receive six
intravenous injections of radium-223 every four weeks
in 50 kBq/kg doses. Other concomitant therapies
were permitted, such as AA, ENZ or denosumab. The
primary endpoints of the study were overall survival
and safety. Only 58% of patients were administered
with the six injections of radium-223. After a median
follow-up period of 7.5 months, the authors reported
an improvement of overall survival rates in patients
taking radium-223 in combination with either ABI,
ENZ, ENZ and ABI, or denosumab. The same benefit
was not observed in patients who were administered
with radium-223 and bisphosphonates. Tolerance
for the treatment was good with only 21% of patients
suspending the treatment due to side effects. The
most common side effect was grade 3 anaemia (12%)
and grade 3–4 combined cytopenia (anaemia, throm-
bocytopaenia, leukopenia and neutropenia), which
were observed in 20% of subjects. Given the relatively
short follow-up period (7.5 months), the possibility
of delayed or persistent marrow toxicity under these
combinations is still to be determined.
We believe that the number of radium-223 doses
and infusions needed in this combined therapy could
be lower than those currently approved for mono-
therapy. At the same time, it is yet to be determined
whether this combination could lead to the occurrence
of a form of PC which is highly resistant to the treat-
ment, given the potential biological alteration of the
tumor or the development of resistance (AR-V7) [12].
Our patient comfortably met the inclusion criteria
set up for the pivotal trial (ALSYMPCA) [1]. Following
a good response to AA treatment, the sequential ENZ
therapy did not prove to be effective, leading to rapid
clinical, biochemical and radiological progression.
After this, the patient began radium-223 treatment with
a good clinical response to pain, which was reduced
after the first dose. Furthermore, no bone-related
events arose, which was of considerable benefit to the
patient’s quality of life. Moreover, the side effect profile
during the treatment was acceptable and easily man-
aged by the clinician.
CONCLUSIONS
Although treatment for mCRPC is changing rapidly,
there are still many open questions regarding the opti-
mal treatment sequence. The sequential or combined
use of AA and ENZ is currently not recommended.
We chose this particular sequencing for the patient
because of his characteristics. At said time, there was
little evidence available regarding the AA — ENZ Se-
quencing. Normally, unltil solid evidence is available,
this type of sequencing not apply on our patients.
Radium-223 is a therapeutic option for mCRPC pa-
tients, both as an initial treatment or in cases of resis-
tance towards other treatments, as its action mecha-
nism suggests few chances of crossed resistance
to other agents. The results obtained demonstrate that
radium-223 can be safely combined with AA or ENZ,
148 Experimental Oncology 40, 144–148, 2018 (June)
which are standard treatments for mCRPC patients —
as has been proven by this particular case — with little
and manageable side effects.
At the same time, these results can be applied
to asymptomatic patients, who were not analyzed
as part of the ALSYMPCA pivotal study. In our opinion,
radium-223 should feature in the early stages of our
therapeutic algorithm, and be administered before
patients develop extra-osseous disease.
The emergence of new therapies against mCRPC
is expected soon, which means that the challenge
will be to learn how to combine and sequence these
agents. Ongoing studies, along with the additional
information expected from the studied biomarkers,
will help us refine our selection of suitable treat-
ments [13].
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