I'd say that NeuroEndocrine differentiation / dedifferentiation is a terminal event in many Prostate Cancers, and probably, it's better addressed as if it were an Small Cell Cancer originating in any place, first as SCLC, but there is also some published work about the use of protocols such as Temozolomide plus Capecitabine, for Pancreatin NE tumors, I guess any Oral Fluoropyrimidine may be susbtituted for Cape in this regimen, this TMZ + Xel was proven efficacious even in low grade, low Ki-67 index Pancreatic Neuroendocrine Tumors.

From a theoretical point of view, one may consider measuring Chromogranin A and also requesting an Octreoscan if Chromogranin is proven high, thus being some kind of a marker for the NE end-stage of Prostate Ca, but this is just speculative. The combination of Everolimus and TMZ has activity also in NeuroEndocrine tumors of Pancreatic origin, and so did Sunitinib. In Lung NE tumors, the combined assessment of Ki-67 proliferation Index and CD56 helped distinguish SCLC from other NE tumors better than Synaptophysin and Chromogranin. The panel of PSA, NSE, Chromogranin A, CD56 and Synaptophysin was used in a case of Prostate NE tumor by Ke-Ichiro Uemura et al, who treated the case with ChemoRT with CisPt and Ifosfamide.

Lapuk AV et al in J Pathol 2012 described the molecular pathology and a mechanism driving the NeuroEndocrine phenotype in Prostate Cancer; Matei DV et al in Clin Genitourin Cancer Sept 2012 proposed a systematic diagnostic attempt for CRPC with NeuroEndocrine differentiation, and Beltran H et al in Cancer Discov 2011 Nov wrote about Molecular characterization of NE Prostate Ca and identification of new drug targets.

Chen H et al in Endocr Relat Cancer May 2012 stated that Pathogenesis of Prostatic SCC involves inactivation of the P53 tumor supressor pathway, and Dr Manuel Constenla-Figueiras, now in Pontevedra, Spain, worked in the 80's on a Gene Therapy for H&N Carcinoma that involved P53.

Fenner A wrote in Nature Rev Urol Dec 2011 about RNA sequencing identifies gene signature of Neuro Endocrine differentiation of Prostate tumors, and in the not so rare event of carcinomatous meningitis from Prostate Cancer, that many times involves a NeuroEndocrine pathology, there are some reports of variably successful use of IT or by Ommaya or other reservoir of Depocyte, however Median Survival for these patients may be no longer than 1-2 months, and sometimes local toxicity of Depocyte is high, even not reaching the sad event of Herpetic Encephalitis, were the use of Acyclovir rescues patients from the portion that would have died, at the cost of increasing the number of patient that survive with severe neurologic deficits, and no changes in the number of patients that survive with no residual neurologic damages.

It's not too much related with the issue of NeuroEndocrine differentiation of Prostate Cancer, but, even when many publications say that Ara-C is not efficacious in Progressive Multifocal LeukoEncephalopathy by JC / SV 40 virus, I had a patient with a CAT diagnosis of this, he had previously 3 lines of CT for a Nodular Sclerosing Hodgkin's Lymphoma, who improved greatly from a clinical point of view after 5 days of 24 h Continuous Infusion of Ara-C at 100 mg/day, the literature proposed dose was 100 mg/m2/day , but a reduced dose was employed considering the highly immunesuppressant nature of Ara-C and the baseline condition of immunesuppression that may suspected in such a HL patient.

Even when more common that one may think, Neuro Endocrine differentiation of Castration Resistant Prostate Cancer remains a clinical problem with not very much that can be considered an standard of care, and if it's diagnosed incidence were higher, it would be a condition to consider multicenter Clinical Trials, how often patients with this end-stage change in Prostate Cancer are not diagnosed because a new biopsy is not performed remains obscure to me. Salut †

This patient has a poor prognosis but has had a plateau in his cancer with a PSA decline on carboplatin and etoposide and relative quiescence of his cancer for six months afterwards.

I would go back to carboplatin and etoposide.

A recent manuscript from Aparicio et al http://www.ncbi.nlm.nih.gov/pubmed/23649003 defines some anaplastic phenotypes and response to two regimens of chemotherapy: docetaxel + carboplatin and cisplatin + etoposide. With these patients response is often transient or ongoing chemotherapy limited by bone marrow suppression. We really need a non-myelosuppressive agent for these patients - unfortunately, we don'f have anything get.

Thank you Dr David for the relevant reference and for your opinion. I was thinking of repeating the carboplatin and etoposide because he was free of progression for around 6 months following the last cycle, but I was hesitant because some colleagues suggested zytiga or Jivtana. I am not sure if these agents will work in patients with those anaplastic phenotypes, and will appreciate any opinion regarding any advantage of Zytiga or Jivtana in this setting.

Patients with anaplastic prostate cancer do not consistently have responses to deeper androgen receptor pathway blockade with Ketoconzole, abiraterone or novel AR blockade. Our experience with cabazitaxel is limited and it may have an effect but I would be inclined to use carboplatin + etoposide first and keep cabazitaxel in reserve. I am not sure there is an entirely correct answer in a complex and difficult case such as this one.

I'd say that NeuroEndocrine differentiation / dedifferentiation is a terminal event in many Prostate Cancers, and probably, it's better addressed as if it were an Small Cell Cancer originating in any place, first as SCLC, but there is also some published work about the use of protocols such as Temozolomide plus Capecitabine, for Pancreatin NE tumors, I guess any Oral Fluoropyrimidine may be susbtituted for Cape in this regimen, this TMZ + Xel was proven efficacious even in low grade, low Ki-67 index Pancreatic Neuroendocrine Tumors.

From a theoretical point of view, one may consider measuring Chromogranin A and also requesting an Octreoscan if Chromogranin is proven high, thus being some kind of a marker for the NE end-stage of Prostate Ca, but this is just speculative. The combination of Everolimus and TMZ has activity also in NeuroEndocrine tumors of Pancreatic origin, and so did Sunitinib. In Lung NE tumors, the combined assessment of Ki-67 proliferation Index and CD56 helped distinguish SCLC from other NE tumors better than Synaptophysin and Chromogranin. The panel of PSA, NSE, Chromogranin A, CD56 and Synaptophysin was used in a case of Prostate NE tumor by Ke-Ichiro Uemura et al, who treated the case with ChemoRT with CisPt and Ifosfamide.

Lapuk AV et al in J Pathol 2012 described the molecular pathology and a mechanism driving the NeuroEndocrine phenotype in Prostate Cancer; Matei DV et al in Clin Genitourin Cancer Sept 2012 proposed a systematic diagnostic attempt for CRPC with NeuroEndocrine differentiation, and Beltran H et al in Cancer Discov 2011 Nov wrote about Molecular characterization of NE Prostate Ca and identification of new drug targets.

Chen H et al in Endocr Relat Cancer May 2012 stated that Pathogenesis of Prostatic SCC involves inactivation of the P53 tumor supressor pathway, and Dr Manuel Constenla-Figueiras, now in Pontevedra, Spain, worked in the 80's on a Gene Therapy for H&N Carcinoma that involved P53.

Fenner A wrote in Nature Rev Urol Dec 2011 about RNA sequencing identifies gene signature of Neuro Endocrine differentiation of Prostate tumors, and in the not so rare event of carcinomatous meningitis from Prostate Cancer, that many times involves a NeuroEndocrine pathology, there are some reports of variably successful use of IT or by Ommaya or other reservoir of Depocyte, however Median Survival for these patients may be no longer than 1-2 months, and sometimes local toxicity of Depocyte is high, even not reaching the sad event of Herpetic Encephalitis, were the use of Acyclovir rescues patients from the portion that would have died, at the cost of increasing the number of patient that survive with severe neurologic deficits, and no changes in the number of patients that survive with no residual neurologic damages.

It's not too much related with the issue of NeuroEndocrine differentiation of Prostate Cancer, but, even when many publications say that Ara-C is not efficacious in Progressive Multifocal LeukoEncephalopathy by JC / SV 40 virus, I had a patient with a CAT diagnosis of this, he had previously 3 lines of CT for a Nodular Sclerosing Hodgkin's Lymphoma, who improved greatly from a clinical point of view after 5 days of 24 h Continuous Infusion of Ara-C at 100 mg/day, the literature proposed dose was 100 mg/m2/day , but a reduced dose was employed considering the highly immunesuppressant nature of Ara-C and the baseline condition of immunesuppression that may suspected in such a HL patient.

Even when more common that one may think, Neuro Endocrine differentiation of Castration Resistant Prostate Cancer remains a clinical problem with not very much that can be considered an standard of care, and if it's diagnosed incidence were higher, it would be a condition to consider multicenter Clinical Trials, how often patients with this end-stage change in Prostate Cancer are not diagnosed because a new biopsy is not performed remains obscure to me. Salut †

Dear Jose Gros, thank you so much for the valuable information. Neuroendocrine differentiation of prostatic adenocarcinoma is something that we have to consider in late cases of castrate resistant/ hormone refractory metastatic prostate cancer, that become unresponsive to therapy, metastasize to uncommon sites, or when the bulk of disease and rate of progression do not parallel the level/ rate of rise in PSA. In these situations it is advised to repeat the biopsy which can show the neuroendocrine or small cell differentiation as you stated.This is usually a late event.

In the currently presented case, the patient had neuroendocrine differentiation, atypical metastatic sites and aggressive disease at initial presentation and not during the course of his metastatic prostate cancer, this probably reflects a worse prognosis, I guess.

I agree with your comments and with the comment of Dr. David, I will treat this patient with repeat of the platinum and etoposide chemotherapy because he demonstrated initial response and remained free of progression for at least 6 months following the last cycle. I may also use the lines that are used for neuroendocrine tumors upon progression, including capecitabine and Temozolomide, or Temozolomide and everolimus or probably irinotecan regimens as in SCLC if the patient can tolerate additional lines in the near future.

I will set with the pathologist and discuss the case again, so that we may do Ki-67 and CD 56 on his specimen.

Thank you again Dr. David and Dr. Jose for the valuable comments.

Dear Colleagues,

It is interesting that the carbo+ETO combination had a stabilizing effect especially since CDDP+Taxol combination frequently fails for these patients. It is quite likely that the stabilization was due to the hormone ablation and/or etoposide. One option to consider might be the use of etoposide as a single agent (similar to a regimen used in SCLC patients). In adenocarcinoma patients with endocrine differentiation, other agents with single agent activity include Vinorelbine. For an elderly patient single agent etoposide or Vinorelbine with palliative intent might be more appropriate than a platinum regimen at active dose levels. As these patients frequently develop bleeding complications during terminal stage, it is very important to involve the transitional care and hospice care teams earlier than later.

A few references of interest:

http://www.medicalnewstoday.com/releases/81297.php

‎Deliu-Victor Matei et al. Clinical Genitourinary Cancer, Vol. 10, No. 3, 164-73, 2012

Dear Dr Fatih Uckun,

Thank you for the comment. There is no doubt that the aim of our treatment is palliative. The palliative team is actually involved in the care of the patient. As you mentioned, using single agent may be appropriate, in this setting, I would prefer to use etoposide as the single agent chemotherapy. Using single agent or combination of agents will depend on his performance status and the expected toxicity related to the regimen.

Dear Samer

If you decide to use etoposide you may want to use a daily 100 mg dose. Remember its absorption is better in acidic juice like orange juice. Pharmacologically you can also use a BID regimen. A 10 day regimen is not going to be much less effective than a 3 week regimen and will have less chance to cause neutropenia. Some prefer using a small dose of decadron like 2 mg daily when treating primary neuroendovrine malignancies. If you use daily Kytril nausea will not a a problem. if patient unexpectedly has loose stool you may want to consider Zofran instead. I am not sure if you have an MR cholangipgram showing patency of major ducts but remember that etoposide at that reduced dose level still may present an issue if patient develops icterus. Most will not use chemo in a jaundiced patient before bilirubin levels are normalized via percutaneous plastic stents. This may also beca good time to make phone calls to family members so they can be with their loved one.

As etoposide is aTopo 2 inhibitor, it is generally believed you can still use Lupron.

Primary neuroendocrine malignancies of the prostate are ver ver rare while in almost every prostate cancer patient you will see some neuroendocrine diff in a minority of cells. If patient has brothers or sons you may want to have a surveillance plan for them.

If this is a really primary neuroendocrine cancer of the prostate it will progress rapidly in the liver like small cell bladder cancer does. That is why no treatment is generally also considered an appropriate option. if I was the patient, that would certainly be my option.

Dear Samer,

Here is a 2013 review article on oral etoposide that might be helpful. As you know many would use oral etoposide with palliative intent according to a 2 week on 4 week off regimen. http://www.degruyter.com/view/j/raon.2013.47.issue-1/raon-2013-0008/raon-2013-0008.xml?format=INT.

In regards to the PK, you may find our 2001 paper interesting: http://informahealthcare.com/doi/abs/10.3109/10428190109064588

http://www.degruyter.com/view/j/raon.2013.47.issue-1/raon-2013-0008/raon-2013-0008.xml?format=INT

Dear Samer,

If your patient has poor bone marrow reserves due to past Carbo-ETO regimen, even oral etoposide can cause severe neutropenia. The onset would be around day 10-14. Post chemo G-CSF maybe necessary.

You may also find the attached meta-analysis about preemptive use of oral antibiotics instructive

http://jco.ascopubs.org/content/16/3/1179.abstract

Dear Fatih,

Thank you so much for the information and the references. I have used oral etoposide as palliative treatment for patients with small cell lung cancer and for some patients with metastatic sarcomas; the drug is generally tolerable and dose limiting toxicities are infrequent.

If the patient performance status did not allow delivery of combination chemotherapy, including a platinum plus etoposide or other combination regimens, I may use oral etoposide.

I've always had the hunch that, in tumors were host immune condition has an influence on outcomes, Sipuleucel is an evidence that this is the case for CRPC, when considering a prophylactic use on Hematologic Stimulating Factors, GM-CSF may be a better option than G-CSF, as PSA itself seems blunting immune responses in Prostate Ca patients.

1. J Urol. 2002 Aug;168(2):741-7.

Prostate specific antigen inhibits immune responses in vitro: a potential role in

prostate cancer.

Kennedy-Smith AG, McKenzie JL, Owen MC, Davidson PJ, Vuckovic S, Hart DN.

Urology Department and Haematology Research Group, Christchurch Hospital and

Molecular Pathology, Canterbury Health Laboratories, Christchurch, New Zealand.

PURPOSE: Prostate specific antigen (PSA) is found in high concentration in

prostate tissue and in semen, in which its physiological function appears to be

liquefaction. In prostate cancer the peripheral PSA concentration is elevated,

which may be used as a disease marker. Systemic and local immune defects have

been demonstrated in prostate cancer and we postulated a role for PSA in this

immunosuppression. We explored the effects of PSA on human T-lymphocyte

proliferation in vitro.

MATERIALS AND METHODS: PSA was purified from normal seminal plasma using a

modified chromatographic technique. The effect of PSA or control protein on

lymphocyte responses to mitogens, tetanus toxoid and alloantigens was tested. The

inhibitory effect observed was further explored by varying the time of PSA

addition, denaturing PSA and including interleukin-2 and anti-PSA antibodies.

RESULTS: PSA suppressed in vitro phytohemagglutinin and alloantigen stimulated

lymphocyte proliferation in a dose dependent manner. This effect was reversed by

adding anti-PSA antibodies but not by interleukin-2.

CONCLUSIONS: These in vitro PSA effects suggest another T-lymphocyte mediated

immunosuppressive mechanism. In vivo high levels of PSA may compromise natural

immune responses to cancer and current attempts at immunotherapy for prostate

cancer

PMID: 12131362 [PubMed - indexed for MEDLINE]

1. Lancet Oncol. 2012 May;13(5):509-17. doi: 10.1016/S1470-2045(12)70007-4. Epub

2012 Feb 10.

Combined immunotherapy with granulocyte-macrophage colony-stimulating

factor-transduced allogeneic prostate cancer cells and ipilimumab in patients

with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation

trial.

van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar

RJ, van der Sluis TM, Gall HE, Harding TC, Jooss K, Lowy I, Pinedo HM, Scheper

RJ, Stam AG, von Blomberg BM, de Gruijl TD, Hege K, Sacks N, Gerritsen WR.

Department of Medical Oncology, VU University Medical Centre, Amsterdam,

Netherlands.

Comment in

Lancet Oncol. 2012 May;13(5):440-2.

Immunotherapy. 2012 Jun;4(6):577-80.

BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced

allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against

prostate cancer; preclinical studies have shown potent synergy when combined with

ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to

assess the safety of combined treatment with GVAX and ipilimumab in patients with

metastatic castration-resistant prostate cancer (mCRPC).

METHODS: We did an open-labelled, single-centre, dose-escalation study of

ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion

phase, both at the VU University Medical Centre (Amsterdam, Netherlands).

Eligible patients had documented mCRPC and had not been previously treated with

chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX

intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells

every 2 weeks for 24 weeks. The vaccinations were combined with intravenous

ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort

received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our

primary endpoint was safety. This study is registered with ClinicalTrials.gov,

number NCT01510288.

FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not

record any severe immune-related adverse events at the first two dose levels. At

the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3

hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis

and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic

effect). Due to observed clinical activity and toxic events, we decided to expand

the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0

mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom

developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and

one grade 3 hepatitis--all immune-related adverse events. The most common adverse

events noted in all 28 patients were injection-site reactions (grade 1-2 events

seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and

pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in

prostate-specific antigen from baseline was recorded in seven patients (25%); all

had received 3·0 mg/kg or 5·0 mg/kg ipilimumab.

INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for

patients with mCRPC. Further research on the combined treatment of patients with

mCRPC with vaccination and ipilimumab is warranted.

FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society

(KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID: 22326922 [PubMed - indexed for MEDLINE]

1. J Immunol. 2012 Dec 15;189(12):5590-601. doi: 10.4049/jimmunol.1201744. Epub 2012

Nov 14.

Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by

CTLA-4 or IL-35 blockade.

Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG.

University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA.

Regulatory T cells play important roles in cancer development and progression by

limiting the generation of innate and adaptive anti-tumor immunity. We

hypothesized that in addition to natural CD4(+)CD25(+) regulatory T cells (Tregs)

and myeloid-derived suppressor cells, tumor Ag-specific Tregs interfere with the

detection of anti-tumor immunity after immunotherapy. Using samples from prostate

cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase

(PAP) and a trans-vivo delayed-type hypersensitivity (tvDTH) assay, we found that

the detection of PAP-specific effector responses after immunization was prevented

by the activity of PAP-specific regulatory cells. These regulatory cells were

CD8(+)CTLA-4(+), and their suppression was relieved by blockade of CTLA-4, but

not IL-10 or TGF-β. Moreover, Ag-specific CD8(+) Tregs were detected prior to

immunization in the absence of PAP-specific effector responses. These

PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was

decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35

reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+)

T cells also suppressed T cell proliferation in an IL-35-dependent,

contact-independent fashion. Taken together, these findings suggest a novel

population of CD8(+)CTLA-4(+) IL-35-secreting tumor Ag-specific Tregs arise

spontaneously in some prostate cancer patients, persist during immunization, and

can prevent the detection of Ag-specific effector responses by an IL-35-dependent

mechanism.

PMID: 23152566 [PubMed - indexed for MEDLINE]

1. Adv Exp Med Biol. 2008;617:581-7. doi: 10.1007/978-0-387-69080-3_60.

Gonadotrophin releasing hormone-based vaccine, an effective candidate for

prostate cancer and other hormone-sensitive neoplasms.

Junco JA, Basalto R, Fuentes F, Bover E, Reyes O, Pimentel E, Calzada L, Castro

MD, Arteaga N, López Y, Hernández H, Bringas R, Garay H, Peschke P, Bertot J,

Guillén G.

Center for Genetic Engineering and Biotechnology of Camaguey, Camaguey, Cuba.

Prostate growth, development, functions, and neoplastic transformation is

androgen dependent. Estrogens have similar effects in the ovary and breast.

Previous studies using gonadotrophin releasing hormone (GnRH/LHRH) vaccines have

shown the usefulness of immunization against this hormone in prostate (PC) and

breast cancer (BC). We have synthesized a peptide mutated at position 6 and

attached to the 830-844 tetanic toxoid (TT) helper T cell sequence in the same

synthesis process. After repeated pig immunizations, we have demonstrated a

vaccine that significantly decreased testes size (p < 0.001), prostate (p

All participants have made highly intelligent and well-founded suggestions, so I will only add the following options (and I will not be always excessively constrained to solely the neuroendocrine / small-cell prostate carcinoma (SCPCa) context (but I do focus on it) although there is plausibility of applicability in all cases discussed, most directly):

(1) Despite the usual cisplatin versus carboplatin debate continuing in some malignancies (and settled for some others as I have elsewhere argued for the higher efficacy of cisplatin in certain cancers), and the widespread use of the "standard" of etopside + carboplatin, cisplatin may still be a pursuable option based on the positive MD Anderson Phase II trial results [1] - 61% response (partial) rate - of that combination in patients with small-cell prostate carcinoma (SCPCa) [note: the addition of doxorubicin to that regimen only escalated toxicity without improving outcome], and also the considerations raised in the case study from Alfredo Berruti's team [2]. Note however that the MDA trial was with a less challenging population than that in the more recent GETUG P01 Phase II trial [3] where carboplatin (+ etoposide) was used instead, in the second line. In that trial, objective response was low and toxicity high in admittedly a cohort of highly aggressive neuroendocrine and/or visceral metastasis in mCRPC patients. Nonetheless, the virtue of carboplatin even if arguably at some efficacy disadvantage (and here, the data do not clearly warrant such a conclusion) is that hematological toxicity is tolerable: so in the Institut Gustave Roussy trial [4], although median PFS was short, at 2.1 months (range 0.6–9.6), nonetheless median OS was 19 months, without some high outliers out to as far as 27.7 months, and, assuringly, toxicity, mostly grades 3/4 anemia at 25% and febrile neutropenia in just 2% of patients, was both manageable and tolerable, and in addition significant pain response was observed in 53% (n=15/28) assessable patients.

(2) My colleague Fatih Uckun notes another often overlooked and attractive option, vinorelbine (Navelbine) which has a good track record in the field and is highly tolerable (mainly reversible grade 1 or 2 fatigue (36%)), and with estramustine (Emcyt), it provides quite respectable median OS of 16.1 months in responders [5,6]. So, like platinum-etoposide regimens, it too can provide significant efficacy with a relatively "gentle" AE spectrum and atypically good QoL.

(3) Another option was mentioned by another colleague, Jose Gros, above, that of capecitabine (Xeloda) which I would prefer combined with a platinum, and here we have warrant for an oxaliplatin partner as per the recently reported Spanish Phase II trial [7] in the second line, establishing high activity: median TTP = 14.5 weeks, and overall survival = 24 weeks, with excellent safety (the sole grade 3/4 AE was grade 3 anemia).

(4) I should add that the vinorelbine and capecitabine regimens have an additional appeal here in this case given the development of brain metastasis: as I have documented [8] we have plausible evidence of cross-BBB (blood-brain barrier) capability for both of these agents (albeit more robust for capecitabine, but still convincing for vinorelbine also), and as in most malignancies, CNS mets are often more limiting and prognostically unfavorable than other visceral sites (lung, liver), yet both have good tolerability and patient QoL (as I have documented extensively, capecitabine dosing is downwardly-flexible to assure minimal toxicity without compromising efficacy); for maximal patient QoL, I would favor either vinorelbine with estramustine (Emcyt), which is far more tolerable and less toxic than etoposide, or metronomic capecitabine with oxaliplatin.

(5) TMZ can be an option, as suggested by Jose Gros above, but I would decide based on the details of CNS tumor burden to justify the appreciable toxicity, although if cranial disease is seen to be very aggressive, I have fared well with a tolerable metronomic TMZ schedule.

(6) Finally, we have some sanction for metronomic therapies such as oral cyclophosphamide (CTX) + prednisolone as demonstrated in the recent INSERM trial [9] which demonstrated good efficacy, superb tolerability, and the convenience of an all-oral regimen, while also providing favorable palliative effects on pain in 43% of the patients. Given that both vinorelbine and capecitabine have demonstrable activity in metastatic PC, these two can be given metronomically as an alternative).

In Closing

Clinical trials are sometimes also an option, with appealing candidate agents like bevacizumab (Avastin), mTOR inhibitors, GEMOX, among others all with molecular promise - but although I have not reviewed them, it is characteristic for most to have an exclusion for CNS metastases. In closing the above options are as I call them "cross-border", straddling palliative intent with an encapsulated curative posture, the boundaries of which are dictated by maximizing patient QoL.

References

1. Papandreou CN, Daliani DD, Thall PF, et al. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol 2002;20:3072-3080.

2. Vignani F, Russo L, Tucci M, et al. Why castration-resistant prostate cancer patients with neuroendocrine differentiation should be addressed to a cisplatin-based regimen. Ann Oncol 2009; 20(12):2019-20.

3. Fléchon A, Pouessel D, Ferlay C, et al. Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial. Ann Oncol 2011; 22(11):2476-81.

4. Loriot Y, Massard C, Gross-Goupil M, et al. Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features. Ann Oncol 2009; 20(4):703-8.

5. Nakabayashi M, Sartor O, Jacobus S, et al. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int 2008; 101(3):308-12.

6. Nakabayashi M, Ling J, Xie W, Regan MM, Oh WK. Response to vinorelbine with or without estramustine as second-line chemotherapy in patients with hormone-refractory prostate cancer. Cancer J 2007 Mar-Apr; 13(2):125-9.

7. Gasent Blesa JM, Giner Marco V, Giner-Bosch V, Cerezuela Fuentes P, Alberola Candel V. Phase II trial of oxaliplatin and capecitabine after progression to first-line chemotherapy in androgen-independent prostate cancer patients. Am J Clin Oncol 2011; 34(2):155-9.

8. Kaniklidis, C. CNS Metastasis from Breast Cancer – New Promise: A Review. [Publication pending (available on my ResearchGate profile)].

9. Ladoire S, Eymard JC, Zanetta S, et al. Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 2010; 30(10):4317-23.

If a Platinum-based Combination Chemotherapy is envisaged in this case, may I suggest to test the concept stated in the Platinum as anticancer drug question elsewhere in this site, of using 5-FU, or 5-FU oral analogue, for example, Capecitabine or S-1, before the Platinum infusion? Probably, doses of FU would be better being reduced for using it this way, I'd suggest for the first course a 33% reduction from the standard FluoroPyrimidine doses when combined with 5-FU in regimens such as those proposed by Al-Sarraf (Pt->5-FU) or Hitt (Docet->Pt->5-FU), this would allow having data from the tolerability of this Combined CT in this individual patient, and ascertain to which extent doses could or should be increased in the following courses.

As it's well stablished that, for example, in Comb CT for Ovarian Epithelial Cancer, Taxane must precede Platin to obtain the best results, is somehow surprising to me that nobody has ever tested in real world conditions, the concept of dosing FluoroPyrimidines in advance to Platinum compounds when used in combination, if regimens as Pt + Taxane + FU are used, the most efficacious and tolerable order of Drugs remains to be defined, but probably the doubt would be just about if Taxane must precede or follow the several days of FU in the course, for, it would be clear that Platinum compound should always be dosed the last drug in the combo. Salut †

Thank you Dr Jose for the valuable comment. I am not sure if combination chemotherapy regimen should be used for such a patient. the prognosis is generally poor and the main aim is palliation. I actually started therapy with oral etoposide and my best expectations would be stabilization of his disease for couple of months. There is a room for many choices as you and the other colleges suggested, and probably using sequential singles agents have the same influence on survival as using combination chemotherapy, with the advantage of less toxicity.

I am thinking to review the data of these patients at our center focusing on the second line chemotherapy following docetaxel failure, as we used to manage them similar to prostate cancer cases without neuroendocrine features, and most of them received docetaxel as the first line chemotherapy option as this patient, and will compare efficacy and survival outcomes with variety of agents following docetaxel failure.

M Quintela-Fandino et al in BR J Ca, 2013, reported about in vivo RAF signal transduction as a potential BioMarker for Sorafenib efficacy in pts with NE tumors, they used Sorafenib combined with Metronomic Cyclophosphamide, and 50 mg CPM a day, p.o. in the morning may be good for a NE tumor, some used this drug with good results at the same continuous 50 mg absolute daily dose in the evenings for CRPC, the doubt may be about the presence of CPM metabolites in Bladder during night increasing the GU side effects of CPM, but CPM at these doses is an extremely well tolerated drug, and eventually another possibility worth considering in such type of patients.

Hi Jose,

While cyclophosphamide single dose is rather nontoxic at that dose level, we observed marked hematologic toxicity when it was used at 100 mg dose level daily for 5 days - even though the patients were heavily pretreated relapsed ALL patients. I would be very cautious about using it beyond a few days. The other potential concern with cyclophosphamide is the less recognized fact that it causes capillary leak with potentially fatal pericardial effusion observed in initial toxicity trials. In patients with neuroendocrine malignancy, a cytokine storm would be potentially complicated by the toxicity profile of cyclophosphamide. I was first informed about this toxicity of cyclophosphamide by Dr. Steinherz at MSKCC back in 1995. Here is a link I saw today: http://www.ehealthme.com/ds/cyclophosphamide/capillary+leak+syndrome

One of the patients of my GP practice, who was an associate in medical oncology in the Madrid Ramon y Cajal hospital, presented some years ago in a SEOM congress, the results of their group with CPM 50 mg p.o. hs, in refractory prostate cancer, good palliation at a negligible toxicity was reported, but your remark is appropriate, 50 mg is not the same as 100 mg, and with alkylating agents, you always need being cautious about long lasting Bone Marrow Aplasia, we may call it: 'burnt BM', I'll try to retrieve the abstract, and put it here, thanks for your attention

Hi!: below please find the link to the abstracts of the 2007 National SEOM Congress in Madrid, Spain, you can look at the 'Analisis retrospectivo de la administración metronómica de CPM y Dexametasona en pacientes con cáncer de próstata hormono-resistentes' first author M Lopez-Garcia, Auditorium 2, Viernes 2, Conferencia 2. [Retrospective analysis of the administration of Metronomic Cyclophosphamide and Dexamathasone in patients with Hormone-Resistant Prostate Cancer'] Any web translator would change the Spanish text into readable English, but as I guess most web translators in translating, for example, Latvian into Hindi would translate first into English, then English into the other language, traductions made this way aren't trustable, probably you're aware of the tale about one of the first computerized translation systems ever built, as a test, their builders proposed translating an English sentence into Russian, and then make the back translation, the sentence was: 'Spirit is strong, but flesh is weak', the back translation said: 'Vodka was good, but Goulash was impossible to be eaten'. Regards.

Salut †

http://www.seom.org/es/congresos/reuniones-seom/anteriores/1571-xi-congreso-nacional-seom

One more!

1. Mod Pathol. 2013 Jul 12. doi: 10.1038/modpathol.2013.105. [Epub ahead of print]

A 92-gene cancer classifier predicts the site of origin for neuroendocrine

tumors.

Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Huang VJ, Erlander MG, Brachtel EF,

Dry SM.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

A diagnosis of neuroendocrine carcinoma is often morphologically

straight-forward; however, the tumor site of origin may remain elusive in a

metastatic presentation. Neuroendocrine tumor subtyping has important

implications for staging and patient management. In this study, the novel use and

performance of a 92-gene molecular cancer classifier for determination of the

site of tumor origin are described in a series of 75 neuroendocrine tumors (44

metastatic, 31 primary; gastrointestinal (n=12), pulmonary (n=22), Merkel cell

(n=10), pancreatic (n=10), pheochromocytoma (n=10), and medullary thyroid

carcinoma (n=11)). Formalin-fixed, paraffin-embedded samples passing multicenter

pathologist adjudication were blinded and tested by a 92-gene molecular assay

that predicts tumor type/subtype based upon relative quantitative PCR expression

measurements for 87 tumor-related and 5 reference genes. The 92-gene assay

demonstrated 99% (74/75; 95% confidence interval (CI) 0.93-0.99) accuracy for

classification of neuroendocrine carcinomas and correctly subtyped the tumor site

of origin in 95% (71/75; 95% CI 0.87-0.98) of cases. Analysis of gene expression

subsignatures within the 92-gene assay panel showed 4 genes with promising

discriminatory value for tumor typing and 15 genes for tumor subtyping. The

92-gene classifier demonstrated excellent accuracy for classifying and

determining the site of origin in tumors with neuroendocrine differentiation.

These results show promise for use of this test to aid in classifying

neuroendocrine tumors of indeterminate primary site, particularly in the

metastatic setting.Modern Pathology advance online publication, 12 July 2013;

doi:10.1038/modpathol.2013.105.

PMID: 23846576 [PubMed - as supplied by publisher]

1. Turk J Gastroenterol. 2012;23(5):427-37.

Systemic treatment of neuroendocrine tumors with hepatic metastases.

Demirkan BH, Eriksson B.

Department of Internal Medicine, Division of Medical Oncology, Dokuz Eylül

University School of Medicine, İzmir, Turkey. [email protected]

Neuroendocrine tumors, 1-2% of all malignancies, are relatively slow-growing

neoplasms. The majority of neuroendocrine tumors belong to the World Health

Organization Group 2 with well-differentiated endocrine carcinomas, but some

tumors can be aggressive. The most common are

gastroenteropancreatic-neuroendocrine tumors, followed by bronchopulmonary

neuroendocrine tumors; less frequent locations are the ovaries, testis and

hepatobiliary locations. They can be either non-functioning tumors with symptoms

related to mass effects and malignant tumor disease or functioning tumors with

specific hormones/neuropeptides autonomously secreted to induce specific clinical

syndromes. Localized neuroendocrine tumors are less frequent than metastatic

ones; in fact, up to 75% of patients with small bowel neuroendocrine tumors and

30-85% of pancreatic neuroendocrine tumors present with liver metastases either

at the time of diagnosis or during the course of the disease. The predominant

metastatic site is the liver, which is the best prognostic marker of survival

regardless of the primary site. If surgical resection or interventional therapies

of the hepatic tumor burden are not feasible, or if the metastases are not

confined to the liver, systemic treatment remains the only option. None of the

systemic therapies is liver-specific, but rather acts on all metastatic sites.

The lack of prospective studies comparing different treatment modalities in

homogeneous cohorts of patients makes the best treatment strategy poorly defined.

Standard systemic therapy options are somatostatin analogues (octreotide and

lanreotide), interferon-α and chemotherapy. Somatostatin analogues not only

control symptoms related to functioning tumors but tumor growth as well. Because

of the studies challenging its efficacy, as well as the potential for side

effects, the more widespread acceptance of interferon-α in the treatment of

metastatic neuroendocrine tumors has been limited. Well-differentiated

neuroendocrine tumors do not show high sensitivity to chemotherapy because of

their low mitotic rates, high levels of antiapoptotic protein bcl-2 and increased

expression of the multi-drug resistant gene. Traditional chemotherapeutic agents

are streptozotocin in combination with 5-fluorouracil or doxorubicin, or to some

extent dacarbazine. Temozolomide, capecitabine and oxaliplatin, as monoagents or

in combination therapy, show efficacy in phase II trials. Patients with poorly

differentiated neuroendocrine tumor, regardless of the primary tumor

localization, are candidates for cisplatin and etoposide chemotherapy regimen.

Peptide receptor radionuclide therapy is reported to be an effective treatment

option for patients with good performance status and high somatostatin-receptor

scintigraphy uptake as well as without major liver involvement. Basic fibroblast

growth factor, vascular endothelial growth factor, platelet-derived growth

factor, transforming growth factor alpha and beta, insulin-like growth factor

type 1, epidermal growth factor, stem cell factor (c-kit), and corresponding

receptors have been shown to be expressed in Neuroendocrine tumors. Current phase

II-III clinical trials with molecular-targeted therapies revealed promising

agents such as everolimus (RAD001), an oral mTOR inhibitor, and sunitinib malate

(SU-11248), an oral multitargeted tyrosine kinase inhibitor against vascular

endothelial growth factor receptors, platelet-derived growth factor receptors,

c-kit receptors, glial cell linederived neurotrophic factor, and FMS-like

tyrosine kinase-3 (Flt 3), which were approved for the treatment of advanced

pancreatic neuroendocrine tumors. Ongoing clinical trials with bevacizumab, a

humanized monoclonal antibody against vascular endothelial growth factor, will

further define the role of angiogenesis inhibitors in advanced intestinal

neuroendocrine tumors. Various further novel strategies of targeted therapy and

microRNA-regulated pathways in neuroendocrine tumors are under development.

PMID: 23161287 [PubMed - indexed for MEDLINE]

1. Expert Opin Pharmacother. 2013 Jun;14(9):1187-203. doi:

10.1517/14656566.2013.796931.

Targeted therapy with kinase inhibitors in aggressive endocrine tumors.

Marotta V, Franzese MD, Del Prete M, Chiofalo MG, Ramundo V, Esposito R,

Marciello F, Pezzullo L, Carratù A, Vitale M, Colao A, Faggiano A.

Federico II University, Department of Clinical Medicine and Surgery, Italy.

[email protected]

INTRODUCTION: Kinase inhibitors (KIs) are a class of anticancer drugs that

inhibit activity of the enzymes protein kinases, which regulate crucial cellular

processes and have a demonstrated role in human oncogenesis. Treatment of

advanced forms of endocrine cancer which are not responsive to cytotoxic

chemotherapies is challenging and use of KIs is gaining a growing role in this

field.

AREAS COVERED: The authors summarize the main genetic alterations known to be

linked to endocrine tumors, indicating the rationale for utilizing KIs.

Furthermore, they present an updated analysis of clinical trials available on

PubMed Central, which were pertinent to the activities of KIs in aggressive

endocrine cancer. The authors also discuss the adverse effects of KIs and

summarize likely involved underlying mechanisms.

EXPERT OPINION: KIs are effective in obtaining a radiological disease control and

an improvement of progression-free survival in several forms of endocrine cancer

but will never deliver a knockout blow of the disease, due to mechanisms of

adaptation to circumvent the specific molecular blockade. The new frontier of KIs

treatment is to identify agents that could synergize activity of KIs. The true

goal will be to perform an overall genotyping of each tumor, thus predicting the

impact of combined targeted therapies in the context of a particular

constellation of mutant genes.

PMID: 23675883 [PubMed - in process]

Dear Jose,

Nice references !,

Regarding the first study ; the 92 gene classifier, how could identification of the primary site of those neuroendocrine tumors influence the decision of therapy ? It is my opinion that identification of the primary site will not help much in the setting of metastatic neuroendocrine carcinomas. Therapeutic options are guided by the degree of differentiation and Ki-67.

dear Salah: I think your precissions are OK and right, but you never know when data you've obtained may have a practical value, in this case, we may postulate that the activating pathways in a NeuroEndocrine tumor may differ to the ones in a tumor of a similar pathology but of different origin, and from a tumor in an organ to another one in the same organ, this with much less chances of actually happening, and in our days of targeted therapy gaining place, and offering new options almost daily, a surprise may come in the medical literature regarding the way to treat the individual case you are confronted with, when you never suspect, offering new therapy indications, we have a proverb: 'Knowledge doesn't occupy room', and at least it keeps you busy, being bored is very bad to your mental health. Salut †

The article below sounds as not being exactly the subject, but still having some connection

1. Expert Opin Pharmacother. 2013 Jun;14(9):1187-203. doi:

10.1517/14656566.2013.796931.

Targeted therapy with kinase inhibitors in aggressive endocrine tumors.

Marotta V, Franzese MD, Del Prete M, Chiofalo MG, Ramundo V, Esposito R,

Marciello F, Pezzullo L, Carratù A, Vitale M, Colao A, Faggiano A.

Federico II University, Department of Clinical Medicine and Surgery, Italy.

[email protected]

INTRODUCTION: Kinase inhibitors (KIs) are a class of anticancer drugs that

inhibit activity of the enzymes protein kinases, which regulate crucial cellular

processes and have a demonstrated role in human oncogenesis. Treatment of

advanced forms of endocrine cancer which are not responsive to cytotoxic

chemotherapies is challenging and use of KIs is gaining a growing role in this

field.

AREAS COVERED: The authors summarize the main genetic alterations known to be

linked to endocrine tumors, indicating the rationale for utilizing KIs.

Furthermore, they present an updated analysis of clinical trials available on

PubMed Central, which were pertinent to the activities of KIs in aggressive

endocrine cancer. The authors also discuss the adverse effects of KIs and

summarize likely involved underlying mechanisms.

EXPERT OPINION: KIs are effective in obtaining a radiological disease control and

an improvement of progression-free survival in several forms of endocrine cancer

but will never deliver a knockout blow of the disease, due to mechanisms of

adaptation to circumvent the specific molecular blockade. The new frontier of KIs

treatment is to identify agents that could synergize activity of KIs. The true

goal will be to perform an overall genotyping of each tumor, thus predicting the

impact of combined targeted therapies in the context of a particular

constellation of mutant genes.

PMID: 23675883 [PubMed - in process]

Neuroendocrine differentiation is very common in conventional prostatic adenoCa and shouldn't change therapy. From the path review of Gleason 8 with some neuroendocrine diff (can typically see some patchy neuroendocrine marker expression by IHC) the treatment should be as for conventional adenoCa. This is NOT equivalent to having a component of small cell carcinoma, which would require differing chemotherapy. Carcinoid type well differentiated neuroendocrine type tumours such as those of lung or GIT are very rare in prostate and from the description given this doesn't sound like such a case. Ki67 index is only validated in GIT neuroendocrine tumours.

Dr. Williams, you might not have seen some of the earlier comments, including: "Primary neuroendocrine malignancies of the prostate are very very rare while in almost every prostate cancer patient you will see some neuroendocrine diff in a minority of cells." This is a unfortunate patient with multiple mets for whom "no therapy" is an appropriate option and clearly no standard effective treatment based on randomized clinical trials is available. The initial question was about using carboplatin + Etoposide as the patient was treated with that combination and apparently responded. Any suggestions as to how you would treat the patient - or would you treat such a patient with any form of chemotherapy ?

Dear Dr Williams. Your comment is valid, however; we made some clinico-pathologic correlation to decide on his therapy. To start with, his clinical presentation was not typical for the usual case of metastatic prostate cancer. The patient had primary refractory disease that was primary progressive despite LHRH analogue, casodex, and docetaxel. Furthermore, the occurrence of liver and brain metastases early on the course of metastatic disease is more typical for high grade neuroendocrine carcinoma / or small cell carcinoma arising in the prostate. We reviewed the pathology once again after we presented all these data to the pathologist, however; the pathologic diagnosis remained the same (prostate adenocarcinoma with some neuroendocrine differentiation). We decided to treat the patient with platinum and etoposide protocol given all this information, in the absence of level 1 supporting evidence, and the patient responded. I think that future therapy for this particular patient should be adopted from protocols used for high grade neuroendocrine carcinomas based on this unique clinical scenario. I emphasize that there is probably no write and wrong answer given the limited data, and this is the reason why I wanted to share this case to listen to your opinion.

Another publication in the line

1. Int J Oncol. 2013 Sep;43(3):713-20. doi: 10.3892/ijo.2013.1997. Epub 2013 Jun 28.

Substitution of anti-androgens and tegafur-uracil combination therapy for

castration-resistant prostate cancer: Results of a multi-center randomized phase

II study.

Takahashi M, Kawabata R, Kawano A, Murakami Y, Sutou Y, Inai T, Akazawa S, Hamao

T, Hayashi H, Fukawa T, Takemura M, Yamamoto Y, Yamaguchi K, Izaki H, Fukumori T,

Kanayama H.

Department of Urology, Institute of Health Biosciences, The University of

Tokushima Graduate School, Tokushima 770-8503, Japan.

We conducted this study to determine whether substitution with anti-androgen

(SOA) and tegafur-uracil (a pro‑drug of 5-FU) combination therapy is more

effective than SOA alone after relapse from initial hormonal therapy. Patients

who were histologically confirmed and relapsed after initial hormonal therapy

were included. All patients were randomly allocated into two groups: SOA alone

(group A) or SOA combined with tegafur-uracil (group B). The mRNA expression of

four enzymes, including thymidylate synthase (TS), dihydropyrimidine

dehydrogenase (DPD), orotate phospho-ribosyltransferase (OPRT) and thymidine

phosphorylase (TP), in prostate cancer cells was analyzed by quantitative

reverse-transcription polymerase chain reaction. Fifty-two patients were enrolled

in this study. The median age was 77 (range: 47-92) years. The PSA response rate

in group B (61.5%) tended to be higher compared to that in group A (34.6%)

(p=0.095). Group B (median: 15.9 months) had a significantly longer time to PSA

progression (TTP) compared to group A (6.4 months) (p=0.014). In patients with a

lower TS expression or a higher OPRT expression, group B demonstrated a higher

PSA response rate compared to group A (p=0.019 and p=0.041, respectively). In

addition, in the patients with a lower TS expression, group B demonstrated a

significantly longer TTP compared to group A (p=0.018). There were no severe

adverse events in either treatment group. After relapse from initial hormonal

therapy, SOA combined with tegafur-uracil is effective and well tolerated. The TS

mRNA expression level may be a predictive factor for this combination therapy.

PMID: 23817692 [PubMed - in process]

Dear Dr. Salah:

You have a tough case on your hands. Neuroendocrine prostate tumors are particularly aggressive, and arise against a background of prostate cancer treatment failure or prostate cancer that has been subjected to advanced treatment regimes.

1. Up front, I would like to inform you of a clinical trial using Aurora kinase inibitors that is now recruiting patients at NIH trials.gov (see below). Since these patients with advance neuroendocrine prostate cancer are rare, enrollment may be broad. Also, Danusertib (PHA-739358) is a an Aurora kinase inhibitor with very dramatic results in neuroendocrine prostate tumors, but was originally tried only in leukemia. Danusertib can be got from Nerviano Medical Sciences, in Italy. Nerviano trialed it for many solid cancers, but Aurora inhibitors appear to be specific for prostate cancers with NEUROENDOCRINE features, so a new Aurora kinase inhib is being trialed. Danusertib is already available. See story here : http://www.prostatecancersurvivorspeak.com/targeting-a-tough-type-of-advanced-prostate-cancer-an-exciting-breakthrough/

A Phase II Trial of MLN8237 in Patients With Metastatic Castrate Resistant and Neuroendocrine Prostate Cancer

http://clinicaltrials.gov/show/NCT01799278 NIH Clinical Trials.gov

2. I have found the following papers to be very useful in dissecting the occurrence of NE features in prostate cancers.

http://jco.ascopubs.org/content/30/36/e386.extract

Challenges in recognizing treatment-related neuroendocrine prostate cancer.

J Clin Oncol. 2012 Dec 20;30(36):e386-9

http://www.hindawi.com/journals/pc/2011/543272/

Review of Small Cell Carcinomas of the Prostate

As noted in this paper:

""""For the surgical pathologist, the most critical and common issue concerning the diagnosis of a small cell neuroendocrine carcinoma is its confusion with a poorly differentiated acinar adenocarcinoma (Gleason 5), notably those with a solid pattern without gland formation and central necrosis in a small focus on needle biopsies. Indeed, misdiagnosing small cell carcinomas as high-grade acinar adenocarcinoma seems to occur commonly. Studies reveal a 0.5–2% incidence of small cell carcinoma in patients diagnosed in biopsies as opposed to a 10%–20% figure in autopsies cases [28, 29]."""

Also,

ttp://www.nature.com/aja/journal/v15/n3/full/aja20137a.html

Asian Journal of Andrology (2013) 15, 328–332; doi:10.1038/aja.2013.7; published online 18 March 2013

Neuroendocrine differentiation of prostate cancer

""""""""""""Interestingly, every single case of prostatic adenocarcinoma also contains scattered NE tumor cells........ The reported incidence of prostatic SCNC is low (~1% of all prostate cancers), but this disease is likely significantly underdiagnosed.17 A main reason is that patients with known prostatic adenocarcinoma whose diseases have become advanced and widely metastatic on imaging studies usually do not undergo tissue diagnosis. Another reason is that SCNC is morphologically very different from prostatic adenocarcinoma and often metastasizes to visceral organs, while adenocarcinoma typically involves bone and lymph nodes. As a result, a connection between metastatic SCNC and the original prostatic adenocarcinoma may not always be established" ... The caveat is that these patients may have had a pre-existing undiagnosed adenocarcinoma which has been completely replaced by the rapidly proliferating tumor cells of SCNC.""""""""""""

http://emedicine.medscape.com/article/1611899-overview#a30

Pathology of Small Cell Prostate Carcinoma

3. Your choice of carboplatin and etoposide is considered a unusually effective treatment for NE prostate cancer. As described here: http://annonc.oxfordjournals.org/content/20/12/2019.2.full

4. Is there chromogranin A in plasma?

Best of luck to you and God's blessing on your patient.

There's something new everyday, even when degree of connection may not always be too high.

Clin Endocrinol (Oxf). 2013 Jun 24. doi: 10.1111/cen.12270. [Epub ahead of print]

Are serotonin metabolite levels related to bone mineral density in patients with

neuroendocrine tumours?

Sen Gupta P, Grozinsky-Glasberg S, Drake WM, Akker SA, Perry L, Grossman AB,

Druce MR.

Department of Endocrinology, Barts & the London School of Medicine, QMUL, London,

UK.

BACKGROUND: Bone mineral density (BMD) is influenced by multiple factors. Recent

studies have highlighted a possible relationship between serotonin and BMD.

Patients with neuroendocrine tumours (NETs) frequently have elevated urinary

5-hydroxy-indoleacetic acid (5-HIAA) levels, a serotonin metabolite. Evaluation

of the relationship between 5-HIAA and BMD in patients with NETs may provide

insights into the relationship between serotonin and BMD.

METHODS: One-year audit of consecutive patients with NETs within two

institutions. Relationships between urinary 5-HIAA and dual X-ray absorptiometry

(DEXA)-scan-measured BMD were investigated by group comparisons, correlation and

regression.

RESULTS: Of 65 patients with NETs, 19 did not participate or were excluded. Of 46

subjects evaluated (48·9% males, 63·8 ± 10·5 years, BMI 26·6 ± 4·4 kg/m(2) ) with

32 gastrointestinal, 9 pancreatic, 3 pulmonary and 2 ovarian NETs, 72·3% had the

carcinoid syndrome. Median interval from diagnosis was 4·0 years (IQR 2·0-6·0);

41·3% had osteoporosis and 32·6% osteopaenia (WHO definition). The group with a

higher urinary 5-HIAA had a lower hip BMD (total T-score and Z-score), confirmed

on individual analysis (Spearman's rank correlation -0·41, P = 0·004; -0·44,

P = 0·002, respectively); urinary 5-HIAA was not found to be an independent

predictor for BMD on multiple linear regression analysis.

CONCLUSION: These data of patients with NETs with higher serotonin metabolites

having a lower BMD at the hip in group and individual comparisons, warrants

further evaluation. Urinary 5-HIAA measurement alone cannot be used to predict

future BMD. A larger cohort with prospective design including fractures as a

clinical outcome will aid these data in determining whether patients with NETs

should be subject to targeted osteoporosis prevention.

© 2013 John Wiley & Sons Ltd.

PMID: 23790044 [PubMed - as supplied by publisher]

This is the link to a recent CME activity on NETs offered by MedScape, but this is supposedly available without having to request help in ResearchGate, you'll tell us.

www.medscape.org/viewarticle/808325

NeuroEndocrine Tumors do have differences, and these differences may represent a different sensitivity pattern, the abstract below points to a Gene study to ascertain the origin of a NET, but even when in this case the origin is know, Prostate, having that kind of information may have a value when you don't expect to.

Mod Pathol. 2013 Jul 12. doi: 10.1038/modpathol.2013.105. [Epub ahead of print]

A 92-gene cancer classifier predicts the site of origin for neuroendocrine

tumors.

Kerr SE, Schnabel CA, Sullivan PS, Zhang Y, Huang VJ, Erlander MG, Brachtel EF,

Dry SM.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

A diagnosis of neuroendocrine carcinoma is often morphologically

straight-forward; however, the tumor site of origin may remain elusive in a

metastatic presentation. Neuroendocrine tumor subtyping has important

implications for staging and patient management. In this study, the novel use and

performance of a 92-gene molecular cancer classifier for determination of the

site of tumor origin are described in a series of 75 neuroendocrine tumors (44

metastatic, 31 primary; gastrointestinal (n=12), pulmonary (n=22), Merkel cell

(n=10), pancreatic (n=10), pheochromocytoma (n=10), and medullary thyroid

carcinoma (n=11)). Formalin-fixed, paraffin-embedded samples passing multicenter

pathologist adjudication were blinded and tested by a 92-gene molecular assay

that predicts tumor type/subtype based upon relative quantitative PCR expression

measurements for 87 tumor-related and 5 reference genes. The 92-gene assay

demonstrated 99% (74/75; 95% confidence interval (CI) 0.93-0.99) accuracy for

classification of neuroendocrine carcinomas and correctly subtyped the tumor site

of origin in 95% (71/75; 95% CI 0.87-0.98) of cases. Analysis of gene expression

subsignatures within the 92-gene assay panel showed 4 genes with promising

discriminatory value for tumor typing and 15 genes for tumor subtyping. The

92-gene classifier demonstrated excellent accuracy for classifying and

determining the site of origin in tumors with neuroendocrine differentiation.

These results show promise for use of this test to aid in classifying

neuroendocrine tumors of indeterminate primary site, particularly in the

metastatic setting.Modern Pathology advance online publication, 12 July 2013;

doi:10.1038/modpathol.2013.105.

PMID: 23846576 [PubMed - as supplied by publisher]

GFP labeled prostate cancer markers: http://www.protean.cz/en/recombinant-proteins/cancer-markers