Brain Metastases From Prostate Cancer

An Emerging Clinical Problem With Implications for the Future Therapeutic Scenario

Orazio Caffo; Antonello Veccia; Lucianna Russo; Enzo Galligioni

Future Oncol. 2012;8(12):1585-1595.

Abstract and Introduction

Abstract

Brain metastases from prostate cancer (PC) seem to be more frequent than in the past, possibly because advances in the treatment of patients with castration-resistant PC have prolonged their survival. Furthermore, docetaxel (the drug of choice for the first-line treatment of castration-resistant PC) cannot cross the blood–brain barrier and control metastatic foci. However, this problem may be overcome by new active drugs such as cabazitaxel.

Introduction

Prostate cancer (PC) is the most common non-skin cancer among men and the second leading cause of cancer death in the USA, where 240,890 affected men were newly diagnosed and 33,730 died in 2011.^[1] The incidence and mortality rates in Europe in 2008 were similar.^[2] Radical treatment of localized disease (prostatectomy, external radiotherapy and brachytherapy) can lead to the long-term survival of many patients and, even in the presence of nonlocalized disease, androgen deprivation therapy allows the disease to be controlled as long as it remains sensitive to hormonal treatment. Unfortunately, although the response to hormonal manipulation is quite favorable, this usually lasts no more than 2–3 years, and the patients eventually progress despite castration.

The unfavorable evolution of PC is related to various molecular mechanisms that allow cancer cells to escape hormonal control^[3] and lead to the transition from hormone-sensitive to castration-resistant disease. Little has changed in the treatment of hormone-sensitive PC, which is still limited to androgen deprivation alone or combined with androgen receptor blockers, but the treatment of castration-resistant PC (CRPC) has undergone revolutionary changes over the last decade. Until a few years ago, nonhormonal strategies (chemotherapy with mitoxantrone) were only palliative^[4,5] but this changed in 2004 when it was discovered that docetaxel significantly improved symptom control and survival,^[6,7] although post-docetaxel disease management remained an unmet medical need. However, over the last 2 years, a number of drugs with different mechanisms of action have been found to improve survival in the post-docetaxel setting: cabazitaxel (a new chemotherapeutic agent),^[8] abiraterone (a new androgen-deprivation agent),^[9] Sipuleucel-T (a vaccine)^[10] and enzalutamide (a new androgen receptor blocker).^[11] As a whole, these approaches have changed (and are still changing) the natural history of PC, and have considerably improved the survival of patients with CRPC.

Brain metastases (BMs) are the most frequent intracranial neoplasms in adults. Their estimated incidence in the USA is 200,000 cases per year^[12] with 8–10% of patients developing symptomatic BMs.^[13,14] BMs are common during the course of various types of cancer, mainly lung (40–50%) and breast cancer (15–25%) and melanoma (5–20%).^[13,14] Patients with BMs have a poor prognosis, and most live for only 4–6 months after diagnosis owing to the very limited survival benefit of the available treatments.^[15]

BMs should be distinguished from other CNS metastases. The term BM should be limited to the focal seeding of the brain parenchyma (parenchymal BMs) and not used in the case of secondary lesions involving the leptomeningeal and pachymeningeal (dural) compartments; dural metastases can be further divided into epidural and subdural lesions.

The symptoms of BMs are usually related to intracranial hypertension and frontal lobe syndrome (headache, paresis and seizures), but many patients present confusion, weakness, aphasia, visual disturbances or ataxia, which may be confused with symptoms of ischemic or hemorrhagic events. However, a correct differential diagnosis can be made using improved radiological techniques.

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Table 1. Summary of reported cases of brain metastasis from prostate cancer.
Study (year)	Cases (n)	BMs (n)	Diagnosis tool	Treatment	Time since PC diagnosis	Survival after BM diagnosis	CRPC condition	Ref.
Demierre and Berney (1983)	10	Multiples	Clinic	SC	NA	NA	NA	[86]
Zhang et al. (1997)	1	1	CT	S	24 months	19 months	No	[87]
Fervenza et al. (2000)	1	1	NMR	S + XRT	NA	8 months	Yes	[88]
Behrens et al. (2001)	1	1	NMR	S	9 years	NA	NA	[89]
Minami et al. (2001)	1	Multiples	NMR	Gamma knife	NA	NA	No	[90]
Tsai et al. (2001)	2	Case 1: 1	NMR	S + XRT	144 months	37 months	NA	[91]
		Case 2: 1	NMR	S	48 months	12 months	Yes
Erasmus et al. (2002)	1	1	CT	S + XRT	0	4 months	No	[92]
Saito et al. (2006)	1	1	NMR	Hormonal therapy	0	NA	No	[93]
Chiang et al. (2004)	2	Case 1: 1	CT	S	77 months	3 weeks	Yes	[94]
		Case 2: 1	CT	S	48 months	21 months	No
Salvati et al. (2005)	13	1 in 11 cases Multiples in two cases	CT and NMR	S + XRT	NA	9.2 months median survival (eight patients)	NA	[23]
Confavreux et al. (2006)	1	Multiples	NMR	SC + XRT	84 months	4 months	Yes	[95]
Grenader et al. (2007)	1	1	NMR	S + XRT	0	10 months	No	[96]
Chitale et al. (2008)	1	Multiples	CT	S + XRT	0	12 months	No	[97]
Castro Gomez et al. (2009)	1	1	NMR	S + XRT	15 months	6 months	Yes	[98]
Sweets et al. (2009)	1	1	NMR	S	48 months	60 months	No	[99]
Roberts-Thomson et al. (2009)	2	Case 1: multiples	CT	S + XRT	120 months	NA	Yes	[100]
		Case 2: 1	CT	S	60 months	NA	Yes
Gokoz Dogu et al. (2011)	1	Multiples	CT	SC + XRT	36 months	4 months	No	[101]

BM: Brain metastasis; CRPC: Castration-resistant prostate cancer; CT: Computed tomography; NA: Not assessed; NMR: Nuclear magnetic resonance; PC: Prostate cancer; S: Surgery; SC: Supportive care; XRT: External radiotherapy.

Sidebar

Executive Summary

The Development of Brain Metastases in Prostate Cancer Patients

The 'seed and soil' theory may be applied to prostate cancer (PC) brain metastasis (BM) development, with the possibility of having a dormant period.
The clinical mechanism of true BM development is hematogenic spread.

The Incidence of BMs in PC Patients

Autopsy series overestimate the incidence of BMs.
Two old and large studies found an incidence of 0.63–0.7%.
A recent study of castration-resistant PC (CRPC) patients found an incidence of 2.3%.
The difference should be critically viewed because of the different patient selection criteria.
The increasing trend of BMs has been confirmed by a recent single-institution observation.

Molecular Mechanisms of BM Development in PC Patients

Specific molecular features could favor the development of BMs, including the expression of KLF6-SV1, reelin and HER2.

Relationship Between the Incidence of BMs & Improved Survival

An increased incidence of BMs has been observed in various types of tumors and the availability of new active drugs has increased the chances of patient survival.
The introduction of docetaxel into clinical practice doubled or tripled the chance of survival in CRPC patients.

The Ability of Drugs to Penetrate the Blood–Brain Barrier

The blood–brain barrier (BBB) is the main obstacle to the penetration of most drugs into the brain parenchyma and, in other types of tumors, this has greatly influenced their activity against BMs.
Docetaxel, the only approved first-line chemotherapeutic agent in CRPC, has been been found to have only a limited ability to penetrate into brain tumor tissue because of its P-gp activity.

Local Treatments for PC BMs

Surgery and radiotherapy should be proposed whenever possible to patients with a good performance status, controlled systemic disease, solitary large lesions and those with a life expectancy of more than 3 months.

Implications for Therapeutic Scenarios in PC

The inability of docetaxel to cross the BBB together with its ability to improve the survival of CRPC patients should be considered crucial issues in BM development.
Cabazitaxel has proved to be active in docetaxel-pretreated patients and is capable of penetrating the BBB.
Abiraterone has proved to be active in docetaxel-pretreated patients and reaches brain concentrations that are five- to nine-times its concentration in blood.
There are no data concerning the ability of new therapeutic agents, such as Sipuleucel T or enzalutamide, to cross the BBB.