NcXHF

THE SPECTRUM OF NEUROENDOCRINE TUMORS
with AR independence and PD-NEC have only recently been
recognized.
The incidence of NEPC is not well established because obtaining
repeat biopsies in patients with metastatic prostate
cancer has not been common practice. Autopsy series suggest
PD-NEC may be present in up to 10% to 20% of men
dying of metastatic castration-resistant prostate cancer
(CRPC). Emerging data from the biopsies of metastases from
patients with CRPC treated with the potent AR targeted therapies
abiraterone or enzalutamide suggest the incidence may
be rising. 98 This increased incidence could be a result of an
increased recognition, patients living longer, or because of
the effect of novel therapies. In a recent meta-analysis by
Wang et al, which evaluated clinical outcomes of 123 patients
with histologically confırmed NEPC that arose after a history
of prostate adenocarcinoma, the median time of progression
from adenocarcinoma to PD-NEC was 20 months and the
median overall survival of patients with PD-NEC was 7
months. 99 Clinically, PD-NEC is associated with symptoms
of accelerated disease progression often in the presence of
visceral, lytic bone, or unusual sites of metastatic disease; a
disproportionately low-serum PSA relative to the overall
burden of disease; and a limited response to AR-targeted
therapies. 52,96,97,100,101 Uncommonly, NEPC may be associated
with an ectopic production of hormones (such as adrenocorticotrophic
hormone [ADH], antidiuretic hormone,
thyroxine, and with clinical manifestations of thyrotoxicosis),
inappropriate ADH production, hypercalcemia,
and/or adrenal hyperfunction. Elevated serum neuroendocrine
markers (including chromogranin A, NSE, and/or
carcinoembryonic antigen) may help support the diagnosis
but can also sometimes be elevated in CRPC with adenocarcinoma
histology. 102 If PD-NEC is suspected, a
biopsy should be considered to confırm the diagnosis. The
diagnosis and treatment of PD-NEC can be challenging,
and assessment of the clinical context and additional
pathologic review are often recommended before making
treatment recommendations.
Treatment
Few patients with pure NEPC present with localized disease,
and therefore there are limited data on treatment of patients
with organ-confıned disease. These patients are very likely to
have occult metastatic disease not detected on a bone or CT
scan, but PET scans may be useful in confırming localized
disease. 103 For localized PD-NEC, a multimodality approach
similar to SCLC should be considered, which consists of chemotherapy
with concurrent or consolidative radiotherapy.
Very limited data are available regarding the use of surgery in
this clinical setting.
Chemotherapy is commonly used as front-line therapy for
metastatic PD-NEC that either presents as de novo or occurs
after therapy. 95,100 Since PD-NEC can show mixed or hybrid
features (as described above with both PD-NEC and prostate
adenocarcinoma components), androgen deprivation therapy
is also often given either fırst or in combination with chemotherapy,
depending on the clinical context. Platinumbased
chemotherapy regimens (most often with cisplatin or
carboplatin with either etoposide or taxane chemotherapy
[docetaxel or paclitaxel]) are recommended for patients with
aggressive clinical features and predominantly PD-NEC histology.
In a phase II clinical trial of 38 patients with small cell
prostate cancer treated with doxorubicin, cisplatin, and etoposide,
Papandreou et al reported an objective response rate of
61%, although there were no complete responses. 104 This regimen
was associated with greater toxicity as compared to cisplatin
and etoposide alone, and there was no improvement in the
median time to progression (5.8 months) and overall survival
(10.8 months). Most recently, Aparicio et al defıned a clinical
diagnosis of anaplastic prostate cancer by one of seven aggressive
clinical features (including PD-NEC) for inclusion into a
phase II study of carboplatin and docetaxel (CD) followed by
etoposide and cisplatin (EP) on progression. 105 In this study,
65.4% and 33.8% of patients were progression free after four cycles
of CD and EP, respectively. Median overall survival was 16
months (95% CI, 13.6 to 19.0 months). There is no standard
therapy after platinum chemotherapy, and patients are typically
managed according to SCLC guidelines.
Special Considerations
Primary diagnostic challenge. Not all patients with aggressive
androgen independent–CRPC demonstrate clear evidence of
PD-NEC morphology on a metastatic biopsy.
Clinically aggressive tumors in the setting of a low PSA and
poor clinical response to AR therapies (suggestive of AR
independence) do not always demonstrate morphologic features
of PD-NEC. This may be a result of disease heterogeneity
and/or overlapping molecular features. Therefore, tumor
morphology does not always predict clinical behavior. Chemotherapy
including platinum is often considered, based on
studies in anaplastic prostate cancer. The role of alternative
AR therapies in this setting is not known.
Secondary diagnostic challenge. PD-NEC is not always androgen
independent. At times, morphologic features or immunohistochemical
profıles of metastatic tumors suggest
PD-NEC, but AR expression and/or signaling are active. 106
These tumors are often either mixed or show hybrid features
with both AR and neuroendocrine markers present. Clinically,
these are less aggressive than most cases of PD-NEC,
and patients are sometimes recommended for hormonal
therapies. Future molecular markers to distinguish ARdriven
CRPC from AR-independent disease will aid in patient
selection for therapy.
CONCLUSION
Neuroendocrine neoplasms are a diverse group of neoplasms
distinguished by site of origin, functional status, and degree
of aggressiveness. Although a variety of pathologic features
are shared, NETs have largely been classifıed in an organspecifıc
manner and their grading and staging remain sitespecifıc.
Nonetheless, several themes cross organ boundaries.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 99