Chapter 162 Treatment of Castration-Resistant Prostate Cancer 3705

100 Hazard ratio 0.70 (95% CI 0.58-0.83)

P < .001
90

80

70

Survival (%)
60 Radium-223
(median overall
50 survival, 14.9 mo)
40

30
Placebo
20 (median overall
survival, 11.3 mo)
10

0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Months since randomization
No. at risk
Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

Fig. 162.8. Overall survival in the ALSYMPCA study. (Data from Parker C, Nilsson S, Heinrich D, et al.:
Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213–223, 2013.)

KEY POINTS: PALLIATIVE MANAGEMENT
• Patients ith bac pain and a history of bone metastases osteolytic (as opposed to osteoblastic) bone metastasis, and a high
should be evaluated for spinal cord compression. This
clinical syndrome often includes one of the following
signs and symptoms: back pain, focal neurologic deficit
(motor, sensory), or changes in bladder or bowel control.
• nitial management of suspected cord compression markers on immunostaining (diSant’Agnese, 1995; Nelson et al.,
includes immediate MRI of the spine and initiation of
high-dose intravenous corticosteroids. Definitive treatment
should include radiation therapy, surgical decompression,
or both.
• oledronic acid and denosumab are both reasonable similar to that of patients with other neuroendocrine tumors (e.g.,
treatment options for the prevention of skeletal-related
events in patients with castration-resistant bone
metastases. Denosumab may include the advantage of not
requiring renal dosing. Both agents can (rarely) cause ONJ.
• adium is a novel alpha emitting radiopharmaceutical also reported doxorubicin-containing combinations as modestly
that has received FDA approval for the treatment of
symptomatic bone metastases in CRPC patients without
visceral metastases or bulky lymph node disease.
neuroendocrine/anaplastic transformation (diSant’Agnese, 1995;
Nelson et al., 2007). The therapeutic implications of this finding
are of significance because tumors demonstrating this phenotype
usually represent an inherently endocrine-resistant subtype and, in
view of their different clinical and biologic properties compared
with the usual adenocarcinoma of the prostate, these tumors also
require different treatment strategies.
Such tumors possess a number of biologic characteristics unique
to neuroendocrine tumors that can also arise from other organs, most
commonly the lung. Among these are the expression of receptors to
various neuroendocrine peptide growth factors, such as somatostatin,
chromogranin A, and serotonin, as well as PTHrP and TP53 mutations.
These tumors have an uncharacteristic clinical behavior (compared
with the usual metastatic prostate cancer), reflected by frequent visceral
involvement and rapidly growing soft-tissue metastases. Patients
frequently have subacute and often dramatic changes in their disease
pattern characterized primarily by a rapidly growing soft-tissue mass
(frequently involving the primary site but also with retroperitoneal
masses), rapid development of visceral (especially liver) infiltration,
incidence of parenchymal brain involvement (Fig. 162.9). Histologic
evaluation is strongly encouraged. This frequently culminates with
the demonstration of a small cell variant or a poorly differenti-
ated neoplasm on pathology with the presence of neuroendocrine
2007). Interestingly, patients with this tumor phenotype either stop
expressing PSA in the presence of major tumor progression or even
have undetectable PSA levels at the time of this transformation.
Treatment of the neuroendocrine/anaplastic phenotype is often
small cell carcinoma of the lung) and usually includes combinations
of cisplatin and etoposide (Frank et al., 1995), or the combination
of a taxane plus carboplatin (Aparicio et al., 2013, 2017) (please
also see the section on Platinum agents, earlier). One group has
efficacious (Papandreou et al., 2002). Radiation therapy is effective
and should be considered in cases with bulky disease, with brain
metastasis, or when local disease control in critical areas may have
a positive impact on quality of life (pain, potential pathological
fractures, and bladder outlet obstruction). A combined chemotherapy
and radiation therapy approach is frequently necessary to accomplish
maximal disease control. Despite high initial response rates with
chemotherapy and radiation treatment, the prognosis of these patients
remains poor and is dependent on various factors, including extent
and location of metastases. In general, survival is less than 12 months.
CONCLUSION
With more drugs at our fingertips for the treatment of CRPC than
ever before and an increasing number of novel therapeutic targets
being discovered every day, we are still left with several challenges
and unanswered questions. First we must determine how these
approved and experimental therapies should ideally be sequenced
in individual patients with CRPC to maximize the therapeutic benefit.
Second, we need to develop strategies to combine these drugs
optimally in a rational manner, taking advantage of our understanding
of negative feedback loops and alternative pathway activation to