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Neuroendocrine prostate tumors: histologic features and therapy
* Corresponding author: Prof. Francesco Greco
Mailing address: Centro Salute Uomo, via Palma il Vecchio 4/A,
Bergamo, Italy.
Email: francesco_greco@ymail.com
Received: 27 June 2023 / Accepted: 28 June 2023 / Published: 26 September 2023
DOI: 10.31491/UTJ.2023.09.010
Abstract
Neuroendocrine (NE) tumors of the prostate are rare tumors, that can arise de novo but much more commonly occur after androgen deprivation therapy for prostate adenocarcinoma. NE tumors of the prostate are classified into: adenocarcinoma with NE differentiation, well-differentiated NE tumor/carcinoid, small-cell NE carcinoma, large cell NE carcinoma, adenocarcinoma with Paneth cell NE differentiation and mixed NE carcinoma—acinar adenocarcinoma. IHC plays a vital role and should be approached at two levels. For the issue of confirming NE differentiation, markers for NE differentiation include synaptophysin, chromogranin, and CD56. If there is any uncertainty about the histogenesis, that is, whether a tumor is primary to the prostate, markers for prostatic lineage—PSA, PSAP, PSMA, prostein (p501s), NKX3.1, ERG (by IHC or FISH)—may be used. Actually, platinum-based chemotherapy is commonly administered to patients with pure small cell carcinoma based on small cell lung cancer (SCLC) data and the accumulating data for aggressive variants of castration-resistant prostate cancer (AVPC). This may consist of a combination of carboplatin (or sometimes cisplatin) plus either etoposide (based on SCLC) or a taxane (especially if mixed histology or AVPC features). A combination regimen of cisplatin, etoposide, and doxorubicin has been also investigated but the benefit-risk ratio of the three-drug combination was considered unfavorable. Unfortunately, platinum-based chemotherapy often presents high toxicity and a short overall survival. Results of currently ongoing preclinical and clinical studies are expected to enhance our understanding of these tumors’ underlying biology and guide our efforts toward the development of personalized medicine through targeted diagnostic and therapeutic approaches.
Keywords
Prostate cancer, neuroendocrine disease, histologic differentiation, systemic therapies
Introduction
Prostate cancer (PC) is the second most commonly diagnosed cancer in men, with an estimated 1.1 million diagnoses worldwide in 2012, accounting for 15% of all cancers diagnosed [1]. The actual prevalence of PC is at age
< 30 years of 5% [95% confidence interval (CI): 3–8%],
increasing by an odds ratio (OR) of 1.7 (1.6–1.8) per decade, to a prevalence of 59% (48–71%) by age > 79 years
[2]. The incidence of PC diagnosis varies widely between
different geographical areas, being highest in Australia/
New Zealand and Northern America [age-standardized
rates (ASR) per 100,000 of 111.6 and 97.2, respectively],
and in Western and Northern Europe (ASRs of 94.9 and
85, respectively), largely due to the use of prostate-specific antigen (PSA) testing and the aging population. The
incidence is low in Eastern and South-Central Asia (ASRs
of 10.5 and 4.5, respectively), whilst rates in Eastern and
Southern Europe, which were low, have shown a steady
increase [1]. Based on the histological characteristics, PCs
are mostly represented by acinar type adenocarcinoma,
composed of tumor cells with luminal differentiation including the expression of prostate-specific antigen (PSA)
and androgen receptor (AR) [3, 4]. Differently, neuroendocrine (NE) tumors of the prostate are rare, and they usually occur after androgen deprivation therapy for prostate
adenocarcinoma.
NE tumors of the prostate can arise de novo but much
more commonly occur after androgen deprivation therapy
for prostate adenocarcinoma. The influence of androgens
on the prostate gland represents an important risk factor
for the development of PC in different ethnic/racial groups
and androgen deprivation therapy (ADT) combined with
other therapies which target androgen receptor (AR) signaling such as abiraterone acetate or enzalutamide is a
standard first-line approach for metastatic prostate cancer
[5]. Most castration-resistant prostate cancers (CRPC)
are still dependent on AR signaling through acquired
AR gene mutation, amplification, or other means to reactivate the AR [5, 6]. Approximately 15–20% of CRPC
tumors will lose dependence on AR signaling at some
point during their disease course but the identification of
AR-independent disease in the clinic remains challenging. One apparent clinical manifestation is a histologic
transformation from an AR-expressing prostate adenocarcinoma to an AR-negative, poorly differentiated small cell
neuroendocrine carcinoma histology [7, 8]. This cancer
phenotype is often referred to as neuroendocrine prostate
cancer (NEPC) to broadly encompass both pure small cell
carcinomas and mixed adenocarcinoma neuroendocrine
tumor morphologies. AR expression is typically low but
even when AR is expressed, NEPC tumors tend to be less
dependent, or “indifferent”, to canonical AR signaling.
NE cells of the normal prostate
NE cells of the prostate were originally described by Pretl
in 1944 [9]. NE cells with the dual properties of endocrine
cells and neurons, i.e., acting in secretory and autocrine/
paracrine fashions, are widely distributed in normal prostatic acini and ducts. In 1999, Aumuller et al. suggested
human prostate NE cells to be a cell lineage of their own,
being of neurogenic origin and therefore distinct from the
urogenital sinus-derived prostate secretory and basal cells
[10]. There are two types: the open cells with extensions
at their apex that connect with the lumen, and closed cells
with dendritic processes that extend between adjacent
cells, resting on the basal lamina and in close topographical relationship with nerves [11].
NE cells are usually present in the transition zone and
peripheral zone of the prostate than the central zone, suggesting their potential involvement in benign prostatic hyperplasia and PC, respectively [4]. NE cells do not express
luminal differentiation markers AR or PSA but they are
positive for NE markers including chromogranin A (CgA),
synaptophysin (SYN), and neural cell adhesion molecule
1 (CD56) [12].
Actually, we ignore the function of NE cells in the prostate. Nevertheless, these cells express serotonin, histamine, CgA, calcitonin, neuron-specific enolase, which
play a role in the regulation of the prostate epithelium and
sperm function [13].
Pathologic classification of prostate cancer with NE differentiation
In the last decade, the World Health Organization (WHO)
and the Prostate Cancer Foundation (PCF) developed a
histo-morphologic classification of prostate cancer with
NE differentiation, in order to systematically describe this
heterogeneous prostate cancer subtype [13, 14] (Table 1).
Neuroendocrine differentiation (NED) is usually present
in prostatic carcinomas than in other urogenital tumors because NED is a common feature of prostatic adenocarcinomas and is usually determined by immunoreactivity for
neuroendocrine markers (CgA, NSE, or bioactive eutopic
hormones such as somatostatin and 5-HT) [11, 15].
As reported in the literature, NED is present in 30–100%
of all prostate adenocarcinomas, even if there are other
forms of NED associated with small cell carcinomas of
the prostate [11, 15]. According to the new WHO classification system, these are entitled small-cell neuroendocrine carcinoma. The malignant phenotype of NED is
also found in certain carcinoid and carcinoid-like tumors.
However, the most common histopathological pattern is
focal NED in conventional adenocarcinomas of the prostate [11, 15]. It has been suggested that NE tumor cells
could be found at all stages of PC but they don’t express
the androgen receptors (AR) [11, 15].
Table 1
Histo-morphologic classifications of prostate cancer with NE differentiation.
| Histomorphologic classifications | 2016 WHO Classification | PCF Classification |
|---|---|---|
| Adenocarcinoma with NE differentiation | YES | YES |
| Well-differentiated NE tumor/carcinoid | YES | YES |
| Small cell NE carcinoma | YES | YES |
| Large cell NE carcinoma | YES | YES |
| Adenocarcinoma with Paneth cell NE differentiation | NO | YES |
| Mixed NE carcinoma—acinar adenocarcinoma | NO | YES |
Note: NE, neuroendocrine; PCF, Prostate Cancer Foundation; WHO, World Health Organization.
Usual prostate adenocarcinoma with NE differentiation
A usual prostate adenocarcinoma with NE differentiation is referred to prostate adenocarcinoma with acinar or ductal type, in which focal NE cells are appreciable by immunohistochemistry (IHC) alone (i.e., synaptophysin, CD56, and chromogranin). The number of NE cells varies from case to case, but generally comprises no more than 1% of the entire tumor cell population. The detection of NE cells depends on the sensitivity and specification of the antibodies against NE markers such as CgA (the most sensitive and specific used marker) and SYN [4, 16]. Several studies have suggested that the number of NE cells is positively correlated with tumor grade and is particularly high in patients treated with hormonal therapy [4, 17]. However, the clinicopathologic significance of NE cells in prostate adenocarcinoma is still uncertain and the role of NED on prognosis could not be explained.
Well-differentiated NE tumor (carcinoid tumor)
A carcinoid tumor is a classic, well-differentiated NE tumor with a morphology similar to that of carcinoid tumors in other sites, including the lung, gastrointestinal tract, and bladder without arising from the urethra/bladder. Carcinoid tumor arises from NE cells and they are positive for NE markers (SYN, CgA, or CD56), negative for PSA but in some cases, these tumors can be positive for prostate-specific acid phosphatase (PAP) [4, 18]. The diagnosis of carcinoid tumor in the prostate needs to meet the following criteria: 1) the tumor must originate from the prostate parenchyma rather than involvement of the prostate by a tumor arising from other organs; 2) the tumor should be distinct from coexisting adenocarcinoma; 3) the tumor must be positive for NE markers and negative for PSA [13]. True carcinoid tumor of prostate is very rare and some cases with a carcinoid-like appearance but positive PSA staining have been found in the literature and therefore cannot be diagnosed as carcinoid tumor and an alternative diagnosis of adenocarcinoma (with focal NE cells) should be considered [19, 20].
Small cell NE carcinoma
Small cell NE carcinoma (SCNC) is an aggressive, highgrade NE tumor with similar morphologic features to
those of the lung and other organs. SCNC is defined by
characteristic nuclear features, including lack of prominent nucleoli, nuclear molding, fragility, and crush artifact
and necrosis is frequent. Approximately, 40% to 50% of
small cell carcinomas have a history of usual prostatic
adenocarcinoma, with a median interval of diagnosis between the two histological forms of 25 months [13, 21].
Furthermore, SCNCs are generally negative for AR and
PSA. Although most cases of SCNC arise in patients who
have been treated with hormonal therapy for prostate adenocarcinoma, some patients can develop SCNC as a primary tumor in the prostate. Nevertheless, primary SCNC
is rare and comprises less than 1% of prostate cancers [22].
The diagnosis of small cell carcinoma of the prostate is
based on the evaluation of morphologic features which
are similar to small cell carcinomas of the lung. However,
SCNC presents some morphologic variations, such as intermediate cell type, which have slightly more open chromatin and visible small nucleoli in comparison to small
cell carcinoma of the lung [21]. Using IHC techniques,
the small cell component is positive for 1 or more NE
markers (synaptophysin, chromogranin, CD56) in almost
90% of cases, whereas PSA is positive in about 17% to
25% of cases [13, 21]. In 24% and 35% of cases, positivity is noted for p63 and high-molecular weight cytokeratin
markers typically negative in prostatic carcinoma [23].
Considering the rarity of primary small cell carcinoma
of the prostate, it is important to exclude the presence of
metastasis or local extension from other sites such as the
bladder. This differential diagnosis can be performed by
applying the fluorescence in situ hybridization (FISH) or
reverse transcription polymerase chain reaction of a gene
fusion between members of the ETS family of genes, in
particular ERG (ETS-related gene) and TMPRSS2, found in approximately one-half of the usual prostatic adenocarcinomas [24].
The median cancer-specific survival of patients with small
cell carcinoma of the prostate in 191 men according to the
SEER database from 1973 to 2004 was 19 months; 60.5%
of men presented with metastatic disease with a decreased
survival related to the stage; 2- and 5-year survival rates
were 27.5% and 14.3%, respectively [25].
Clinically localized small cell prostate cancer is typically
treated with multimodality therapy based on chemotherapy and radiation similar to limited-stage small cell lung
cancer. In presence of metastases, small cell carcinoma of
the prostate is treated with platinum-based combination
chemotherapy with regimens similar to those used to treat
small cell lung carcinoma. Some experts treat pure smallcell carcinoma with chemotherapy alone, whereas others
add ADT [26, 27].
Large cell NE carcinoma
Large cell NE carcinoma (LCNC) was newly included as a type of NE tumor of the prostate in the 2016 World Health Organization classification of prostate tumors [14]. The tumor cells of LCNC grow as solid sheets, ribbons, or nests with focal microscopic necrosis in the center and areas of peripheral palisading [28]. In contrast to SCNC, the tumor cells of LCNC tend to be large, with a polygonal shape and abundant cytoplasm. Tumor cells of LCNC express one or more NE markers (SYN, CgA, or CD56), with variable expression of PSA, PAP, CK7, and CK20 but they are negative for AR. Ki-67 labeling index often exceeds 50% [29, 30]. Pure LCNC is extremely rare and Evans et al. presented the largest series of seven cases in 2006 [28]. One patient had a primary prostate tumor, and the other 6 cases arose after hormonal treatment of adenocarcinoma of the prostate. The histologic features are identical to LCNC diagnosed in other anatomic sites such as the lung. The outcome is poor, with a mean survival of 7 months after platinum-based chemotherapy.
Adenocarcinoma with Paneth cell-like NE differentiation
Adenocarcinoma with Paneth cell-like NE differentiation is defined as typical adenocarcinoma of the prostate
containing varying proportions of cells with prominent
eosinophilic cytoplasmic granules on routine light microscopy (Paneth cell-like change). Paneth cell-like NE differentiation in prostatic adenocarcinoma can be seen as either patchy isolated cells or diffusely involving glands or
nests [13, 31]. These Paneth cell-like cells may be present
in well-formed glands of Gleason pattern 3 but also can
be present in cords of cells with bland cytology, wherein
strictly applying the Gleason grading system one would
assign a Gleason pattern 5. Although Paneth cell-like NE
differentiation could be found in pattern 5, their bland
cytology, typically limited nature and frequent association
with lower-grade prostate adenocarcinoma suggest not
considering this unique histology as high-grade.
Epstein et al. reported 16 radical prostatectomy specimens
with Paneth cell-like NE cells lacking glandular differentiation. An organ-confined cancer was found in 62.5%
of cases, only 4 cases with seminal vesicle invasion and
none with pelvic lymph node metastases. The postoperative course was also favorable with a > 90% actuarial PSA
progression-free risk at 5 years and the prognosis was
influenced by conventional parameters (i.e., the Gleason
score, T stage, and positive surgical margins) and not by
independent of NE differentiation. Paneth cell-like NE
cells are diffusely positive for NE markers but they may
not express prostate markers.
Mixed NE carcinoma—acinar adenocarcinom
Mixed NE carcinoma—acinar adenocarcinoma is a carcinoma with distinct, recognizable, admixed components of NE (small cell or large cell) carcinoma and conventional acinar adenocarcinoma. Usually, these tumors are represented by mixed small cell carcinoma and adenocarcinoma of the prostate and each of both are readily identifiable as distinctive. As with other unusual subtypes of prostate cancer, a Gleason score is only assigned to the conventional adenocarcinoma component but not to the small cell carcinoma. In reported mixed cases, small cell carcinoma predominated (median: 80% of the tumor), and the Gleason score of the adenocarcinoma was ≥ 8 in 85% of these cases [21]. The presence of concomitant highgrade adenocarcinoma as opposed to lower-grade adenocarcinoma represents an independent predictor of worse cancer-specific mortality. Most patients with mixed small cell carcinoma and adenocarcinoma present with metastatic castration-resistant disease and they are often treated with both ADT and chemotherapy (platinum + etoposide or platinum + taxane).
IHC and FISH in the diagnosis and classification of NE differentiation in prostate cancer
IHC plays a vital role and should be approached at two
levels. For the issue of confirming NE differentiation,
markers for NE differentiation include synaptophysin,
chromogranin, and CD56. Actually, CD57 (Leu7) and
NSE are not more recommended. If there is any uncertainty about the histogenesis, that is, whether a tumor is primary to the prostate, markers for prostatic lineage—
PSA, PSAP, PSMA, prostein (p501s), NKX3.1, ERG (by
IHC or FISH)—may be used.
Additional considerations for the role of IHC include diagnosis, prognosis, and predictive purposes. The formal
utility of Ki-67/MIB-1 IHC is not established; however,
generally observed ranges are outlined in Table 2. The
IHC expression of AR across the proposed subtypes of
NE carcinoma needs to be systematically evaluated such
that its role in the classification of these tumors may be
determined. Promising new molecular targets that may be
amenable to future IHC-based or FISH-based classification and predictive strategies include Aurora A kinase and
N-Myc; however, these markers are not yet validated for
clinical use [13, 32, 33].
Table 2
IHC of NE differentiation in prostate tumors.
| PSA | NE Markers | Ki-67 | |
|---|---|---|---|
| PC | Positive | Scattered + cells | Not increased in NE cells |
| PC with Paneth cell NE differentiation | Variably positive | Diffuse positive in Paneth cells | Few cases studied—not increased |
| Carcinoid-like tumor | Usually positive | Positive | Not studied |
| Carcinoid tumor | Negative | Diffusely positive | Usually low Rarely increased (typically < 5%–20%) |
| SCNC | Usually negative or scattered positive cells | Positive in ~90% of cases | > 50%, typically > 80% |
| LCNC | Usually negative but may be positive | Diffusely positive | Usually > 50% |
| Mixed NE (SC/LC) usual PC | Same as above for each component | Same as above for each component | Same as above for each component |
Note: IHC, immunohistochemistry; NE, neuroendocrine; PC, prostate cancer; PSA, prostate-specific antigen; SCNC, small cell neuroendocrine carcinoma; LCNC, large cell neuroendocrine carcinoma.
Aggressive variants of castration-resistant prostate cancer (AVPC)
Primary small cell NE differentiation is rare with an incidence of less than 2%. Most NED develops in castrationresistant patients following androgen deprivation therapy
[34]. Clinically, treatment-emergent NE/small cell differentiation has been associated with distinct manifestations,
including predominantly visceral or lytic bone metastases
and bulky tumor masses, frequently in the setting of low
PSA levels with high-volume tumor burden [13]. These
tumors are typically not responsive to hormonal therapy,
while they are sensitive to cytotoxic chemotherapy [35].
However, responses are short-lived and overall survival is
reduced. CRPC characterized by one or more of the following was determined to be AVPC:
- histologic evidence of SCPC (pure or mixed), whose
presence determines AVPC regardless of hormonal status;
- the presence of only visceral metastases;
- predominantly lytic bone lesions;
- bulky (5 cm) lymphadenopathy or large (5 cm) highgrade (Gleason 8) tumor mass in prostate/pelvis;
- low PSA at presentation with extensive bone metastatic
disease;
- the presence of NE markers at histology (CgA and synaptophysin) or serum (CgA and gastrin-releasing peptide) combined with either elevated lactate dehydrogenase
(LDH), malignant hypercalcemia or elevated serum carcinoembryonic antigen (CEA);
- progression to CRPC in six months or less after initiation of hormonal therapy.
Patients affected by CRPC should undergo biopsy of accessible metastatic lesions in order to identify NED which
can influence treatment decisions. Recently, Aggarwal
et al. suggested that even patients without “atypical”/
aggressive-variant clinical presentation may harbor tumors with NED and hence diagnostic biopsy of metastatic
lesions may be valuable in all metastatic CRPC (mCRPC)
patients regardless of clinical manifestations [22].
Systemic therapy
In CRPC with small-cell histology, cytotoxic chemotherapy has been associated with improved outcomes and is generally considered the preferred treatment option [36]. Similarly, to small-cell lung cancer, platinum-based chemotherapy regimens are mainly being employed, with cisplatin/etoposide, carboplatin/etoposide, and docetaxel/ carboplatin being the regimens recommended by the NCCN [37]. In patients with clinical AVPC (putting aside pure small-cell histology), there is no clear consensus on the optimal first-line therapy, with 58% of the Advanced Prostate Cancer Consensus Conference (APCCC) 2017 voting in favor of standard mCRPC treatment and 42% of platinum-based chemotherapy [38]. Table 3 summarizes the actual chemotherapy trials in AVPC.
Table 3
Chemotherapy trials in AVPC.
| Study | Papandreou et al. [39] | Loriot et al. [40] | GETUG P01 [41] | Culine et al. [42] | Aparicio et al. [27] | Corn et al. [43] |
|---|---|---|---|---|---|---|
| Study design | Phase 2, single-arm | Phase 2, single-arm | Phase 2, single-arm | Phase 2, single-arm | Phase 2, single-arm | Phase 2, randomized |
| Drug combination | Cisplatin/etoposide + doxorubicin | Cisplatin/etoposide | Cisplatin/etoposide | Cisplatin/docetaxel | Carboplatin/docetaxel (then second-line cisplatin/etoposide) | Carboplatin/cabacitaxel vs. cabacitaxel |
| Patient population | Histologically confirmed SCPC (pure or mixed) | CRPC after docetaxel with or without elevated NSE/CgA | mCRPC with visceral metastasis or elevated NSE/CgA | mCRPC with elevated NSE/CgA | AVPC (per clinical criteria) | mCRPC stratified by presence of AVPC (per clinical criteria) |
| n | 38 | 40 | 60 | 41 | 121 | 160 |
| Efficacy | 36% PSA response 61% OR of measurable disease 84% pain improvement median PFS 5.8 mo median OS 10.5 mo |
23% PSA response 2 out of 5 OR of measurable disease 54% pain improvement median PFS 2.1 mo median OS 19 mo Note*: No association of outcome with NSE/CGA levels |
8% PSA response 9% OR of measurable disease no pain evaluation median PFS 2.9 mo median OS 9.6 mo |
48% PSA response 41% OR of measurable disease 45% pain improvement median OS 12 mo |
47% PSA response (at course
2) 34% OR of measurable disease median PFS 5.1 mo median OS 16 mo |
62% vs. 41% PSA response 57% vs. 21% OR 7.3 mo vs. 4.5 mo median PFS 18.5 mo vs. 17.3 mo median OS Note*: PFS and OS improvement with combination greater in AVPC subgroup (clinical and/or molecular) |
| Safety—Grade 3 –4 AEs > 15% | 100% neutropenia 68% infection 66% thrombocytopenia 34% nausea 26% anemia 21% vomiting |
38% neutropenia (2%
neutropenic fever) 25% anemia |
66% neutropenia (7%
neutropenic fever) 33% thrombocytopenia 27% anemia |
91% neutropenia (17%
neutropenic fever) 34% anemia 17% thrombocytopenia 15% fatigue |
None | 23% anemia 20% fatigue |
| Safety—Toxicityrelated deaths | 3 (sepsis) | None | 1 (febrile neutropenia) | 1 (sepsis) | 1 (sepsis during second-line etoposide/cisplatin) | 1 (thromboembolic event in cabazitaxel arm) |
Note: AVPC, aggressive variant prostate cancer; CgA, chromogranin A; mCRPC, metastatic castration resistant prostate cancer; NSE, neuron-specific enolase; OR, objective response; OS, overall survival; PSA, prostate specific antigen; PFS, progression-free survival; SCPC, small cell prostate cancer. *Results refer to the overall study population (including patients with and without AVPC).
Since the combination of cisplatin with etoposide proved
effective in the treatment of small cell lung cancer, the
same regimen was also suggested for poorly differentiated
NE tumors. Papandreou et al. investigated the efficacy of
a combination of cisplatin/etoposide and doxorubicin in a
phase II trial of 38 patients with histologically confirmed
SCPC (67% pure, 33% mixed) [39]. The benefit-risk ratio
of the three-drug combination was considered unfavorable
in this study and thus the addition of doxorubicin to cisplatin/etoposide was not recommended for clinical practice.
Loriot et al. investigated the combination of carboplatin
with etoposide in a phase II trial of patients with mCRPC
as a second-line therapy after docetaxel [40]. The combination was fairly well tolerated. The median number of
cycles received was three and the median PFS in the overall study population was 2.1 months.
The phase II GETUG P01 examined the combination of
carboplatin/etoposide in patients with anaplastic CRPC
and visceral metastases or elevated serum CgA and/or
NSE [41]. The objective response rate (ORR) was 9%
with 3 patients presenting a partial response and one patient with a complete response. Nevertheless, the toxicity
was high, with 4 patients (7%) presenting febrile neutropenia and one toxicity-related death. Even in this case, the
benefit-risk ratio of this combination was considered to be
not favorable. Of note, the dosage and application mode
of carboplatin and etoposide differed in both studies, with
GETUG P01 employing lower doses of carboplatin (AUC4 vs. 5), but higher doses of etoposide (100 mg/m2
/day i.v
for three days vs. 80 mg/m2
/day i.v. on day 1 and p.o. on
days 2 and 3)—a drug known for its myelotoxicity. Furthermore, the patients underwent 4 cycles in GETUG P01
in contrast with Loriot et al. where they underwent three
cycles.
Finally, the GETUG P01-population had an overall lower
ECOG performance status in comparison to Loriot’s study
(ECOG PS 2 at baseline: 22% vs. 5%), which can explain
the poorer safety profile of this regimen in GETUG P01
and underlines the importance of a good performance status prior to chemotherapy initiation.
Culine et al. investigated the combination of cisplatin with
docetaxel which represents a standard-of-care option in
patients affected by mCRPC [42]. The authors presented a
phase 2 study including 41 mCRPC patients with elevated
serum NSE and/or CGA. Almost half of the patients experienced a PSA response (i.e., PSA decline 50%), and
12 patients (41%) had an objective partial response. The
median OS was 12 months. Unfortunately, 91% of the patients experienced Grade 3–4 neutropenia, and one patient
died from sepsis.
Another phase 2 trial studied the combination of carboplatin/docetaxel in 120 mCRPC patients with clinical AVPC
followed by second-line etoposide/cisplatin as salvage
therapy [27]. A median of four cycles of carboplatin/
docetaxel was administered. A PSA decline 50% at course
2 was achieved in 47% of the patients, while objective
response of measurable disease in 34%. The median PFS
on carboplatin/docetaxel was 5.1 months. The median
overall survival (OS) was 16 months. Toxicity was fairly
manageable overall; most common Grade 3 events were
represented by infection (n=8) and febrile neutropenia
(n=3). Grade 4 events included thrombosis (n=2) and
thrombocytopenia (n=1) and toxicity-related death was
also registered.
Corn et al. conducted a phase 2 randomized trial of cabazitaxel vs. cabazitaxel plus carboplatin in patients with
mCRPC stratified for the presence of AVPC (ca. 55% per
arm) [43]. The platinum-based combination demonstrated
improved efficacy, especially in the AVPC subgroup.
More specifically, median PFS was improved in the combination arm vs. cabazitaxel alone (7.3 vs. 4.5 months),
with prespecified subgroup analysis demonstrating that
the platinum-combination favored only those with clinical AVPC (HR 0.58; 95% CI: 0.37–0.89). Median OS was
similar between the two arms (HR 0.89, 95% CI: 0.63–
1.25, P = 0.50) but the combination regimen was tolerated
fairly well with a median of six cycles received.
Conclusions
NE prostate cancer is an increasingly recognized histologic subtype of PC that most commonly arises in the later stages of the disease as a mechanism of treatment resistance. These tumors are typically refractory to hormonal therapies and, although they usually respond well to platinum-based chemotherapy regimens, the OS of the patients is generally short, with a dismal prognosis overall. Immune checkpoint inhibition with monoclonal antibodies against cancer immune evasion (PD-L1/2, PD-1, CTLA-4) is currently being studied in combinations or alone in several phase 1/2 interventional trials for NE prostate cancer. Results of currently ongoing preclinical and clinical studies are expected to enhance our understanding of these tumors’ underlying biology and guide our efforts towards the development of personalized medicine through targeted diagnostic and therapeutic approaches.
Declarations
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
Francesco Greco is a member of the editorial board of Uro-Technology Journal. The authors declare that they have no conflicts and were not involved in the journal’s review or decision regarding this manuscript.
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