*Corresponding Address: Adrian Pablo Hunis, Assistant Professor of Internal Medicine, University of Buenos Aires, Argentina
How to cite this article: Adrian Pablo H, Melisa H. Prostate Cancer, Update of its Diagnosis and Treatment, with Special Emphasis on its Management
in Argentina. Canc Therapy & Oncol Int J. 2020; 17(5): 555972. DOI:10.19080/CTOIJ.2020.17.555972
Prostate cancer is the second most frequent tumor in men in Argentina. Since the work of Charles Huggins, in 1941, in which he demonstrates that the suppression of the male sex hormone-testosterone-through surgical castration, many years have passed and many advances have been made in terms of diagnosis and treatment of this disease, paradigm of a hormone-dependent tumor. In this work, we intend to summarize the advances and the problems of the disease in the Argentine Republic.
Prostate carcinoma is one of the most frequent tumors in Argentina. As incident cases grouped expressed in percentages,
the prostate represents 9% of new case in the country (GLOBOCAN 2018;) (Figure 1).
Its racial incidence varies significantly, Africans living in the
United States have the highest incidence in the world (224 cases
per 100,000) (Figure 2). The incidence in African Americans is
highly higher than that of White Americans (150 per 100,000),
Western Europeans (39.6 per 100,000), Japanese (8.5 per
100,000), and Chinese (1.1 per 100,000). (Figure 3).
Through the last half of the twentieth century, the annual
incidence of prostate cancer increased slowly but steadily, probably
due to an increase in life expectancy and hence an increase in
the population of men of susceptible age (older than 50 years).
Other factors have also contributed, such as the introduction and
widespread use of PSA (prostate specific antigen) measured in
blood. The PSA identifies a large number of asymptomatic patients
with prostatic carcinoma, the so-called prevalent cases [1-10].
The etiology of prostate cancer is not known. But associated
risk factors are known such as: family history, age, race, diet,
hormonal levels. The more advanced the age, the more possibility
there is of suffering from this pathology. Analyzed the process at
a cellular level, however, the onset of prostate cancer is an early
process, it has been detected in autopsies in the prostates of men
of 20 and 30 years of age. Thus, prostate cancer is defined as small,
microscopic amounts of low-grade carcinoma, found incidentally
in the prostate.
In one study, 20% of men younger than 40 had histological
evidence of prostate cancer.
In contrast, clinically detected prostate cancer at age 40
is rare. The prevalence of both latency and clinically detected
cancer increases significantly with age: 20 to 30% of men over
50 years of age and probably 50% of men over 80 years of age
may have prostate cancer. The majority of clinically detected
prostate tumors are in the seventh and eighth decade of life. The
relationship between latent and clinically detectable is uncertain.
It is not known whether they represent two different entities, or
whether latent prostate cancer is a clinically detectable precursor
to cancer. Other determining risk factors in prostate cancer are
race and geographic origin. As we saw earlier, African Americans
have the highest incidence. In contrast, the lowest incidence rates
are found in Japan and China. As in other tumors, when members
of a racial community move from regions of low incidence to
regions of high incidence, the incidence of prostate cancer
increases in that group. However, genetic factors can be operative
as well. For example, the gene for the androgen receptor (encoded
on the X chromosome) contains a repeating polymorphic CAG
sequence. Several studies indicate that individuals with fewer
repeated CAG sequences in the androgen receptor genes have a
higher risk of developing prostate cancer. In African Americans,
fewer CAG repeat sequences were found than in Hispanics and
Asians. Thus, part of the high incidence of this pathology in African
Americans may be due to this phenomenon. Family history is
related to prostate cancer. The risk increases with the number of
affected relatives. Vasectomy increases the risk of prostate cancer.
The relationship between diet and prostate cancer is probably
very important, although it is difficult to prove given that the
data come mostly from epidemiological studies, rather than
prospective studies. But diet could contribute to the dramatic
difference between western and eastern countries. Important
studies maintain that the content of red meat, animal fat and its
high level of consumption increases the risk. Other factors such as
lycopene, a carotenoid found in tomatoes, lower the risk. Among
the micronutrients and trace elements, selenium, vitamin E, soy
and vitamin D can lower the risk. Other risk factors are exposure
to cadmium: welding, batteries or electrotypes [11-20].
Prostate cancer is a heterogeneous and complex disease that
results from a series of genetic events at the level of the epithelial
prostate cell. These genetic events and many of the environmental
factors that promote tumor development or progression are still
poorly defined. A small group of prostate tumors may derive from
the inheritance of one of several important genes that predispose
to the malignant phenotype and, therefore, confer a high risk of
prostate cancer [21-30].
Familial prostate cancer constitutes an estimated 5-10% of
all prostate cancers and probably as much as 50% of prostate
cancers in men under 55 years of age. Six candidate loci for
familial prostate cancer have been identified; the gene at one of
these loci, HPC-1 (hereditary prostate cancer-1), has been found
to be ribonuclease L (RNase L). The relationship with HPC-1 could
be associated with a more malignant tumor phenotype. Several
genes that participate in the regulation of the cell cycle and in
the regulation of growth factor signaling (Rb, p53, and PTEN),
have been implicated in the development and progression of
prostate cancer. The prevalence of mutations in these genes has
varied from study to study, and the role that genes play in the
development and progression of prostate cancer has yet to be
defined. Also, a variety of proto-oncogenes have been implicated
in the bio pathogenesis of this tumor [31-40].
Although there is strong evidence of a dysregulation of a
variety of growth factors (IGF-1, EGF, PDGF, etc.), also as receptors
to them (Her-2 / neu, receptor to EGF and TGF beta) their exact
roles are not well understood yet. (Figure 4).
The purpose of screening for prostate cancer is to detect
tumor within the gland, potentially curable by definitive local
therapeutics. Historically, the investigation was performed by
digital rectal examination. But, due to the great variations that
exist with the latter, many tumors are not palpable, and most
of the tumors detectable by digital rectal examination are not
confined to the prostate and therefore are not curable. Today
screening is carried out with the measurement of prostate specific
antigen (PSA) in the blood, which greatly increases the detection
of disease confined to the gland.
PSA is a member of the kallikrein family, chemically a
glycoprotein with serine protease activity. It is abundant in
semen, where it is responsible for dissolving the seminal clot. PSA
is produced by both normal and malignant prostate epithelial
cells; production is higher in normal cells. Therefore, conditions
such as benign prostatic hyperplasia, acute prostatitis, elevate
PSA levels. When prostate cancer develops, the serum PSA level
is frequently elevated due to the absolute increase in epithelial
cell volume and possibly the passage of PSA from tissue to serum.
Optimal screening for prostate cancer combines the use of the
PSA test and digital rectal examination. This is because most
tumors are not palpable, and some do not produce enough PSA
to increase the level of serum PSA. PSA test determination can
detect prostate cancer an average of 5.5 years before clinical
detection becomes evident. Most of the tumors detected today by
PSA are non-palpable, asymptomatic tumors that are potentially
curable. The American Cancer Society currently recommends
digital rectal exams and PSA annually for men over 50 years of
age who have a life expectancy greater than 10 years. For the
high-risk group (African American, patient with a family history
of prostate cancer), screening is recommended to start at 40
years of age. Some troublesome topics, however, exist with PSA
testing. Detection of clinically insignificant tumors can lead to
unnecessary treatment for many men. Also, an elevated PSA lacks
Despite the possibility of prostate cancer in men with
moderately elevated PSA levels (4 to 10ng / ml), biopsy in these
cases usually demonstrates benign prostatic hyperplasia rather
than prostate cancer. On the other hand, the majority of cases with
serum PSA levels above 10ng / ml present with prostate cancer,
and their tumors are surely already outside the prostate gland.
The percentage free PSA coefficient is a blood test that measures
the amount of PSA that circulates alone (unconjugated) in the
blood and the amount that is conjugated to other plasma proteins
If the PSA test results are marginal and the percentage ratio
of free PSA is low (25% or less), then it is more likely that we are
in the presence of prostate cancer. If the results of the percentage
free PSA coefficient are normal, even with a marginal PSA result,
the biopsy may be avoided. PSA levels increase with age, and the
use of specific PSA levels adjusted to the same age can increase the
sensitivity of screening for prostate cancer in young people and
increase the specificity of an elevated serum PSA in the elderly.
This strategy is particularly important in young people, in whom
prostate cancer is generally fatal [61-70].
Prostate biopsy is generally performed when a tumor is
suspected by elevated serum PSA, an abnormal rectal examination,
or both. Biopsies are performed transrectally (Figure 5). A
transrectal ultrasound device is inserted into the rectum to view
the prostate during the biopsy. Traditionally, prostate biopsies
are taken in a six-part pattern: bilaterally at the base, in the
middle of the gland, and at the apex. The differential diagnoses
with prostate cancer are: benign hyperplasia, chronic prostatitis,
prostatic lithiasis, TB, granulomatosis, prostatic infarction and
some bladder tumors [71-80].
Most prostate tumors are adenocarcinomas; Small cell
carcinomas and sarcomas may also occasionally be seen.
Adenocarcinomas arise from the glandular epithelium of the
prostate and are frequently multifocal. The diagnosis is frequently
made on the basis of a small portion of glandular material in
relation to the limitations in taking biopsy of it. One of the changes
towards carcinoma is the loss of the basal layer within the glandular
epithelium. Invasion into the surrounding stroma is common and
makes diagnosis easier. In 1966, Dr. Donald F. Gleason published
a systematic classification for grading the pathological features of
prostate cancer. This system is based on the degree of glandular
differentiation of the tumor in which 5 patterns from 1 to 5 are
taken into account that go from the degrees of least aggressiveness
to the greatest, where the score or combined Gleason pattern is
obtained from the sum of predominant patterns in the tumor [81-
In 1993, the WHO recommended the preferential use of
the Gleason classification in the pathology report referring to a
diagnosis of prostate cancer. In 2005, during a Conference of the
International Society of Urologic Pathology (ISUP), a substantial
modification of the Gleason grading system was approved. The
most important changes were related to morphological criteria
to include poorly differentiated glands as a Gleason pattern 4,
and stricter criteria to distinguish the cribriform pattern 4 from
the cribriform pattern 3; as well as recommendations on how to
grade the different variants of prostate cancer and how to report
the Gleason grade in prostate biopsy and radical prostatectomy
The conference concluded with some controversial issues
related to morphology, which remained pending resolution.
The lack of consensus on certain grading problems, advances
in research and changes in the clinical management of prostate
cancer made evident the need to provide solutions. In 2013, Dr.
Jonathan I. Epstein from Johns Hopkins University (JHU) led a
classification proposal in the US that described grades of prognostic
groups (GG1 to GG5) based on biochemical recurrence, based on a
study of 7 869 patients treated by radical prostatectomy at Johns
Hopkins Hospital in Baltimore, between 1982 and 2011, with a
mean follow-up of 2 years (range: 1-8 years). The biochemical
recurrence at 5 years was 95%, 83%, 65%, 63% and 34% in men
with a GG1 to GG5, respectively in biopsy, and 97%, 88%, 70%,
64% and 34% for GG1 to GG5 in radical prostatectomy [101-110].
In 2014, ISUP organized a new consensus conference in
Chicago with the participation of 67 prostate cancer expert
pathologists from 17 countries, and 17 clinicians, including
urologists, radiation oncologists and medical oncologists where
this study was discussed and approved by consensus the new
classification of degrees of prognostic groups. At this conference,
various proposals to update the Gleason scale were also approved,
including the assignment of a Gleason 4 pattern to all cribriform
glands and glomeruloid structures, the grading of mucinous
carcinoma based on the underlying growth pattern. The nongrading
of intraductal carcinoma, the recommendation to report
the percentage of pattern 4 in the Gleason score 7 and the noncommunication
of the tertiary pattern in the prostate biopsy
The final nomenclature for this classification remains to be
approved. Currently, JHU and ISUP have a dispute over this. Johns
Hopkins defends the term “Prognostic Group Grades” and the
ISUP defends the nomenclature “ISUP Grades”. (Figure 6). The
new prognostic group grade classification will help pathologists
improve the classification of prostate cancer based on glandular
morphology. It will also be of use to other clinicians, researchers,
and patients, as it has a better correlation with current disease
management, including active surveillance of patients with lowgrade
Prognostic group grade translation should be fairly
straightforward as it is based on Gleason scores. It is expected that
in the next one or two years, after a period in which cancers are
reported with the old and updated systems, and the institutional
and national databases are adapted, this classification will be
accepted and used regularly in the clinical practice.
The initial symptoms that occur in prostate cancer are:
difficulty starting or finishing urination, reduced force in the
urine stream, dripping at the end of urination, painful or burning
urination, nocturia, painful ejaculation, hematuria. As we can see,
most of these signs and symptoms may well be found in benign
pathologies of the prostate.
Late symptoms in prostate cancer are anemia, uremia, bone
pain (due to bone metastases), hydronephrosis, weight loss,
neurological deficit in the lower limbs (spinal cord compression),
coagulation disorders, hypoalbuminemia. Of these, the minor
symptoms that mark the need for treatment in the patient are
anemia, hypoalbuminemia, and weight loss.
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Clinically inapparent tumor neither palpable nor visible by
T1a Tumor incidental histologic finding in 5% or less of tissue
T1b Tumor incidental histologic finding in more than 5% of
T1c Tumor identified by needle biopsy (for example, because
of elevated PSA)
T2 Tumor confined within prostate T2a Tumor involves onehalf
of one lobe or less
T2b Tumor involves more than one-half of one lobe but not
T2c Tumor involves both lobes T3 Tumor extends through
the prostate capsule
T3a Extracapsular extension (unilateral or bilateral)
T3b Tumor invades seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other than
seminal vesicles, such as external sphincter, rectum, bladder,
levator muscles, and/or pelvic wall (Figure 7)
pT2 Organ confined
pT2a Unilateral, one-half of
one side or less
pT2b Unilateral, involving more than one-half of side but not
pT2c Bilateral disease
pT3 Extraprostatic extension
pT3a Extraprostatic extension or microscopic invasion
of bladder neck
pT3b Seminal vesicle invasion
pT4 Invasion of rectum, levator muscles, and/or pelvic wall
Regional Lymph Nodes (N)
NX Regional lymph nodes were not assessed
N0 No regional lymph node metastasis
1 Metastasis in regional lymph node(s)
pNX Regional nodes not sampled pN0 No positive regional
nodes pN1 Metastases in regional node(s).
Distant Metastasis (M)
a) M0 No distant metastasis
b) M1 Distant metastasis
a) M1a Nonregional lymph node(s)
b) M1b Bone(s)
c) M1c Other site(s) with or without bone disease
a) 1 Tumor found in one or both lobes by needle biopsy,
but not palpable or reliably visible by imaging, is classified as T1c.
b) 2 Invasion into the prostatic apex or into (but not
beyond) the prostatic capsule is classified not as T3 but as T2.
c) 3 There is no pathologic T1 classification.
d) 4 Positive surgical margins should be indicated by an R1
e) descriptor (residual microscopic disease).
f) 5 When more than one site of metastasis is present, the
most advanced category is used. pM1c is most advanced.
g) 6 When either PSA or Gleason is not available, grouping
should be determined by T stage and/or either PSA or Gleason as
Staging in prostate cancer attempts to determine which
tumors are confined to the gland (and are thus curable by local
maneuvers only) and which are not. Prostate cancer spreads to
lymph nodes and bone. Spread to the liver and lung is clinically
more unusual. The staging scheme currently used is as follows:
The iconographic studies are of great importance in the patient
with prostate cancer. If these are performed to stage the patient,
there they manifest their importance. If, on the other hand, the
patient has advanced disease, they will allow us to evaluate the
response to treatment. In the first case, every patient should have
a chest X-ray (f and P), a liver ultrasound, and fundamentally a
whole-body bone scan to evaluate the first metastatic site, which
is the bone (Figure 8).
Magnetic Resonance Imaging (MRI)
(Figure 9) A few years ago, the diagnosis of prostate cancer
was based on screening with prostate-specific antigen (PSA),
which has been used and is used massively until now. On the other
hand, randomized biopsy is the method used to access samples
for histological study. This has led to over-diagnosis and overtreatment
of non-clinically significant lesions (NSC), that is, they
will never produce metastasis and will not put the patient’s life
The over-treatment of these indolent cancers can also
generate a detriment in the quality of life due to intestinal, urinary
and erectile dysfunctions. In order to avoid over-treatment, these
patients began to follow active surveillance protocols. However,
some of them also presented clinically significant lesions (CS)
hidden in places of lesser scope for randomized biopsy, such as
the anterior region of the prostate - that located before the urethra
- and the prostatic apex, and therefore showed an unfavorable
natural evolution, even with the appearance of metastasis. It is
worth remembering that all those with a Gleason score of 7 or
higher are considered CS cancers. This is how another diagnostic
method became necessary that had the ability to diagnose only
The use of magnetic resonance imaging (MRI) of the prostate
dates back to the 1980s, but its main development began around
2007, when articles began to appear with the use of diffusion in
the study of the prostate2,3. Spectroscopy had begun to develop
a little earlier. In 2011 the European Society for Urogenital
Radiology (ESUR) proposed the “Prostate Imaging-Reporting
and Data System version 1” (Pi-RADS v1). In 2014, the “Prostate
Imaging-Reporting and Data System version 2” (PI-RADS v2)4
was released, designed jointly by the American College of
Radiology, ESUR, and the Ad MeTech Foundation, with the aim of
improving the detection and characterization of prostate cancers
through MRI, systematizing the multiparametric MRI (MRI-mp)
technique of the prostate, and also simplifying and systematizing
the reporting of these exams.
After the publication of PI-RADS 2, multiple studies have been
published and some limitations and ambiguities were identified
that are attempted to be resolved with the version 2.1 recently
published in March of this year5.
MRI-mp prostate technique
Prostate MRI-mp requires high-resolution T2-weighted
anatomical sequences, in addition to functional diffusion
sequences (DWI) and contrasting dynamic sequences (DCE). The
T1-weighted sequences are also aggregated to investigate blood
content, nodal and bone metastases. In PI-RADS v2 a sequence
considered dominant for the peripheral zone (DWI sequence)
and a dominant sequence for the transition zone (T2-weighted
sequence) are proposed.
The PI-RADS v2 also details the minimum technical
requirements needed for an adequate MRI-mp. In a 20186 article,
Steven and others studied the adherence of 107 establishments to
the technical parameters of the PI-RADS v2, demonstrating a wide
range of adherence from 20 to 100% for individual acquisition
parameters, concluding that even greater dissemination of these
minimum standards is necessary. It is not the objective of this text
to individualize them, but some points of the functional sequences
will be discussed:
In order to obtain a clear differentiation between nonneoplastic
and neoplastic tissue, at least a high diffusion b
value is required, which in the PI-RADS v2 was established as a
minimum of 1,400. A retrospective study carried out in 2016 by
Rosenkrantz and others showed that b values between 1,500 and
2,500 are optimal for cancer detection, since with these values it
is possible to differentiate inflammatory or fibrotic lesions, which
are “extinguished with high b values”, from neoplastic ones.
Since very high b values are required, the problem of the
low signal-to-noise ratio (SNR) in these sequences arises, and it
is for this reason that in order to perform a good MRI-mp of the
prostate, equipment with a magnetic induction of 3 Tesla or 1.5
Tesla is required, ideally with an endorectal coil, which improves
the signal-to-noise ratio (SNR). In the latest version of PI-RADS
2.1 it is recommended to make acquisitions with a low b set (0
- 100 sec/m m2) and an intermediate one (800-1000 sec/mm2),
with which the ADC Map is calculated. In addition, a high b must
be acquired or calculated, (greater than 1400 sec/mm2), this
value is excluded from the ADC map calculation in order to avoid
the Kurtosis effect.
PET / CT
In recent years, technological advances in some modalities
have made it possible to improve the efficacy and efficiency of
the diagnosis and treatment of prostate cancer. Multi-Parametric
Magnetic Resonance (mpMRI) has been a huge advance in this
regard, also fused image-guided biopsy techniques, etc. But there
has also been a great evolution in the field of Nuclear Medicine,
mainly in the use of PET / CT. In this post we will talk about the
advantages of PET / CT with two different radiopharmaceuticals
in the study of this pathology. A classic bone scan in a patient with
prostate cancer and bone metastases, this low-cost test continues
to be extremely useful.
18F-choline PET / CT: This radiopharmaceutical has
demonstrated superiority in the detection of pathological lymph
nodes and distant metastases compared to other diagnostic
modalities. Diseased tissues show an increase in the uptake or
accumulation of this radiopharmaceutical. 18F-choline is far
superior to the most widely used PET radiopharmaceutical,
18F-FDG, in detecting this type of cancer. This test is usually
requested in patients already treated for prostate cancer, with
elevated levels of the PSA marker in the blood and with other
negative imaging tests such as bone scan or CT.
PET / CT with 68Ga-PSMA: PSMA is a membrane-specific
prostate antigen, it is present in normal prostate tissue, but
increases its concentration in diseased tissue, it is a promising
biomarker not only used in diagnosis but also with potential
therapeutic. By being able to mark with 68Ga, it becomes a very
effective detector of areas in which there are local recurrences or
relapses, affected lymph nodes and distant metastases.
Although it is too early to say so, some studies suggest an
advantage of this tracer over 18F-choline, especially at lower PSA
levels (see bibliography). What is clear is that some images that
are not visible in other modalities are detected thanks to this new
radiopharmaceutical. This advantage is still being investigated and
evaluated. From the technical point of view of the administration
of the radiopharmaceutical and the acquisition of the images, both
mentioned options are relatively simple to implement. In the case
of 18F-choline, a localized acquisition is made in the pelvis a few
minutes after injecting the radiopharmaceutical (5 minutes is
suggested) and another in the whole body after one hour after the
injection. Some hospitals use iodinated contrast in CT acquisition,
while others do not. For the PET / CT study with 68Ga-PSMA,
some authors indicate a single acquisition of the whole body at
the time of administration of the radiopharmaceutical.
Both options mentioned in this article are expensive to produce
and are not yet available in many places. We hope that the effort
in the research and development of these new molecules will have
an impact on the improvement of the staging and post-treatment
assessment of this disease. While the pertinent verifications are
made and their use is generalized, the professionals involved must
prepare us to be up to date with these advances by informing
ourselves and understanding the potential of these techniques.
These iconographic studies are always accompanied by a PSA test
and a complete laboratory routine.
For the patient with advanced disease, in whom the response
to the hormonal and non-hormonal treatments instituted is being
evaluated, the total body bone scan is very important, to visualize if
the pathological hyper uptake points decrease with the treatment,
if the serum levels of PSA decreased or normalized and localized
radiographs for evaluation of osteoblastic metastases and their
evolution during these treatments. It is evident that in advanced
patients, performance status is also an important parameter of
evolution and response to treatment, but with limited (subjective)
When prostate cancer is confined to the gland, both surgery
and radiation therapy are used with success.
However, the important thing in this group of patients also, for
either of both procedures is to reduce morbidity. In the absence
of randomized studies that demonstrate a superiority of surgery
over radiotherapy, decisions are largely made by patients after
Radical prostatectomy has several advantages: examination
of the specimen allows a definitive knowledge of the pathological
stage and degree of the disease. Patients can be stratified according
to the pathological stage of their disease. If the Gleason score is 2
to 4 and the clinical stage is T1c (e.g., the patient has an elevated
PSA without a palpable mass), the survival-free progression rate
after radical prostatectomy is approximately 90%; if the Gleason
score is 5 to 6, the rate is approximately 80%; if the score is 7, the
rate is approximately 55%, and if the score is 8 to 10, the rate is
less than 20%.
For patients stratified as T2, the probability of disease-free
progression at 15 years is approximately 69%.
The higher the Gleason score, the more extensive the disease,
the greater intraoperative and postoperative complications occur.
Intraoperative procedures include bleeding and injury to the
obturator nerve, urethra, rectum, or a major pelvic artery or vein.
Postoperative complications alter the quality of life of the patient,
and are: incontinence, impotence, and ureterovesical stricture. The
incidence of the latter varies between 1 to 9%. The incidence of
incontinence is approximately 8%, with 6% of patients presenting
with stress incontinence and 2% of patients using more than one
diaper per day. Regarding sexual impotence, only 31% of patients
report having an erection and 9% a satisfactory sexual act.
The advantages of external radiation therapy as the primary
treatment for localized disease is that it presents the patient with
a low risk of urinary incontinence and stricture. Radiation therapy
can eradicate tumor extensions around the prostatic capsule, and
when combined with hormone therapy, it offers a chance of cure
for some patients, such as those with intermediate-risk tumors.
The disadvantages of radiation therapy are that the treatment is
long, eight to nine weeks; A special three-dimensional technique
is required that allows the administration of doses of at least 72
Gy, which are those required for correct treatment (Figure 10 &
Also, this treatment does not inform the oncologist about
possible metastases in the lymph nodes, and the long-term
sequelae of high-dose radiotherapy are not known. The Po the
possibility of relapse-free survival after radiotherapy, with the
use of post-treatment PSA levels as a monitoring criterion, can be
predicted by the risk-group of patients at the time of presentation.
For patients with low-risk tumors (stage T1c, Gleason score of 6
or less, and a PSA level of 10 ng / ml or less), the rate is 70 to
80%. For patients with intermediate-risk tumors (stage T2,
Gleason score of 7, PSA between 10 and 20 ng / ml) the rate is
50-55%. In the last decade, the development of conformational
and three-dimensional therapy, which uses computer software to
integrate computed tomography images of the internal anatomy
of the patient in the treatment position, has allowed the volume
of tissue to be a high dose of radiation therapy is administered
to more closely conform to the shape of the tumor. This
advancement has reduced the incidence of both early and late
toxicities in normal tissues and allows higher cumulative doses to
be administered with a reduced risk of late effects. There is now
evidence from randomized and non-randomized studies that a
significant improvement in disease-free relapse rates in patients
with intermediate-risk tumors when doses greater than 70 Gy are
used (Figure 12).
Strict contraindications to external radiation therapy
include: previous pelvic irradiation, active inflammatory bowel
disease, indwelling Foley catheter, severe obesity. The other type
of radiation therapy is brachytherapy or interstitial radiation
therapy, whereby iodine 125 or palladium 103 seeds are
implanted directly into the tumor. This last modality presents a
favorable toxicity profile and promising control rates at 5 and 10
years of follow-up. The downside is that not all centers are trained
in this modality.
Intensity modulated radiation therapy is an advanced form
of 3D-CRT. It constitutes one of the most important technical
advances in recent years, representing a radical change in the
planning and administration of treatment. Like 3D-CRT, IMRT
requires 3D planning with delimitation in axial sections of the
volumes of interest. However, in IMRT, in addition to defining
the goal of total doses needed in the tumor volume, the doctor
establishes the dose restrictions necessary to protect the different
normal tissues involved. According to these indications, the
computer elaborates, based on a calculation algorithm by trial and
error, an irradiation plan that satisfies the required dose profiles.
This optimization process is known as reverse planning.
Intensity-modulated radiation therapy, such as 3D-CRT, uses
multiple beams of shaped radiation that converge on the tumor
target from various entry angles. But unlike it, each treatment
field is formed by the sum of several segments, so that different
levels of dose intensity are generated at the different points of
each field (Figure 1). This effect is achieved with a multilayer
collimator, a device designed to shape the radiation beam using
multiple motorized blocks. The doses delivered by the sum of
the fields creates in the patient a treatment volume in which the
normal organs and tissues are located in restricted areas and the
tumor tissue in the areas of greater exposure (Figure 2).
The use of intensity-modulated radiation therapy has become
popular over the last 15 years and has been rapidly adopted in
multiple centers around the world mainly because of its dosimetric
characteristics, despite a sometimes-incomplete understanding of
its benefits, limitations, and radiobiological implications. and of
the incipient evidence of its potential final clinical benefits. IMRT
has several obvious dosimetric advantages over conventional
2D and 3D conformal radiation therapy. It allows to significantly
reduce the amount of normal tissues subjected to high doses of
radiation, with the potential reduction of the risk of acute and
chronic complications. It is capable of producing much more
homogeneous dose distributions and conformed to the anatomy
of the volumes involved, (Figure 3) reducing the shadow areas at
the limits of the target volume. These factors allow dose escalation
in tumor tissue and a simultaneous reduction in dose in normal
organs, with the consequent increase in the therapeutic range.
Finally, the treatment plan can be designed considering different
dose / fraction for different volumes, allowing to achieve different
radiobiological conditions for normal and tumor tissues that
can improve even more the response. Tumor side and functional
The high degree of precision that can be achieved with the use
of intensity-modulated radiation therapy is the result of a chain
of optimized procedures that begins with the localization of the
tumor in the patient’s body through diagnostic imaging studies,
CT, MRI, PET among others, and is completed with the delivery of
a radiation dose in a course of 30 to 40 therapy fractions. Among
them are the correct delimitation of the target volumes and the
organs at risk, the simulation of the therapy, the calculation
of the doses, the optimization process, inverse or not inverse,
the correct positioning of the patient on the therapy table and
verification with images prior to each treatment fraction. Each of
these links must be made under strict quality control to rule out
any possibility of error. It is necessary to consider that tumors are
not static, being able to present mobility, reduction in size due to
response to treatment, deformations and eventually increase in
volume throughout therapy. Patients may also present changes,
due to edema, variations in body weight, movements of the viscera
or differences in the volume of their contents, in addition to the
movements produced by breathing. These changes determine the
risk that the normal tissues that make up the restriction volumes
may remain positioned in high dose areas during irradiation
and that the tumor target may leave it, determining an increase
in complications and a greater possibility of failure in control.
tumor. These multiple uncertainties, which constitute the main
limitations of IMRT, have led to the development of additional
quality control methods to ensure its correct performance. These
include image-guided radiation therapy (IGRT), respiratory
monitoring, and 4-D radiation therapy. Other limitations of
IMRT that should be considered are the possible inclusion of
large volumes of healthy tissues in areas exposed to low doses of
radiation, determined by the use of multiple treatment fields and
the greater total body exposure due to an increase in the duration
of each treatment. fraction. The consequences of these, which
could be especially important in pediatric patients undergoing
IMRT, have not been established so far.
In recent years, numerous studies have been published that
prove the dosimetric advantages of IMRT. The key question,
however, is what are the clinically relevant advantages that
IMRT has over other conventional techniques? This has been
partially answered by direct and indirect clinical studies that have
determined the existing correlation between the doses received
by each organ and its subsequent function, producing valuable
information on the dose-volume relationships and toxicity for
different tissues, which is currently used in IMRT planning.
There is still no definitive evidence of the clinical advantage
of IMRT in prostate cancer. It is difficult to establish a reliable
comparison between the published studies since they have
differences in radiation techniques, fractionation, definition of
target volume, safety margins, dose restrictions and organs at risk.
In some, the entire pelvis is considered white volume. In others,
only the prostate with or without the seminal vesicles. Historical
controls are used in most comparative studies, which is especially
inappropriate when considering the progress made by diagnostic
procedures and the greater standardization of histology that have
produced a migration of state, or Will Rogers phenomenon. Finally,
adoption of image-guided radiotherapy for patient positioning
and more careful observation of dose-volume-toxicity and doseresponse
relationships may have contributed to the reduction of
toxic effects in IMRT studies. There is, however, some consensus
that IMRT, alone or as part of optimized radiotherapy techniques,
allows dose escalation, reducing the incidence of gastrointestinal
and genitourinary toxicities and the impact on sexual function. For
this reason, IMRT has been included in the NCCN clinical practice
guidelines as a standard of treatment, considering the use of IGRT
if dose escalation is indicated.
In stage T1a, control is performed every 6 months with digital
rectal examination and PSA. In stages T1b and T1c according to
the estimated life expectancy of the patient, if it is considered
that this will be less than 10 years due to comorbidity, the
possibility of controlling it without treatment will be discussed.
If the patient accepts the control and is asymptomatic, he will
remain under observation. If the patient did not accept to control
or have symptoms as a result of your prostate disease, you will
then receive treatment. If the patient is under 80 years of age,
radiation therapy will be indicated, either external (preferably
three-dimensional shaped: 3D) or interstitial (brachytherapy).
Optionally, the urologist can perform radical prostatectomy.
If the patient is older than 80 years, hormone therapy will
be indicated, and optionally either external radiation therapy or
brachytherapy. If it is considered that life expectancy is greater
than 10 years, radical prostatectomy or radiotherapy will be
performed, be it external or brachytherapy.
If the patient presents a Stage T2a with a life expectancy greater
than 10 years, the procedure will be that of radical prostatectomy
or external radiation therapy (3D) or brachytherapy. In any T2 (T2
a, b, c), if a life expectancy of less than 10 years is considered due to
comorbidity: it is discussed with the patient to control it without
treatment. If the patient accepts the control and is asymptomatic,
it is under observation. If the patient does not accept control or
has symptoms, they will receive treatment. If the patient is under
80 years of age, external radiotherapy or brachytherapy will be
indicated at any T2 (a, b, c).
In T2b and T2C with or without prior adjuvant hormone
therapy for 3 to 6 months. Optionally, the urologist can perform
radical prostatectomy. If the patient is older than 80 years,
hormonal therapy will be indicated, optionally radiotherapy in
Stages T2b and T2c. If the estimated life expectancy is greater
than 10 years, radical prostatectomy or radiation therapy, either
external (3D) or brachytherapy, with or without prior neoadjuvant
hormone therapy for 3 to 6 months, will be indicated.
Hormone therapy is indicated in all cases. If the patient is
under 80 years of age: neoadjuvant hormone therapy is indicated
for 3 to 12 months at the discretion of the specialist. After that
period, the patient is reevaluated. If there is a good local response
and the estimated life expectancy is greater than 10 years, radical
prostatectomy or three-dimensional conformal (3D) external
radiation therapy or brachytherapy is indicated. If life expectancy
due to comorbidity is less than 10 years, hormonal therapy can be
continued definitively or preferably conformal external radiation
therapy (3D) or brachytherapy preferably complementary to
external radiation therapy may be indicated. Optionally after
prostatectomy or radiotherapy, adjuvant hormone therapy can be
performed for 3 to 6 months.
If, upon reevaluation of the patient after neoadjuvant therapy,
the local response is insufficient to consider curative treatment,
definitive hormone therapy is indicated. Optionally or if there is
local symptomatic progression, palliative prostate radiotherapy
(preferably 3D) may be indicated. If the patient is older than
80 years, remains in definitive hormonal therapy or if during
definitive hormonal therapy the patient presents symptomatic
local progression, prostate palliative radiotherapy (preferably 3D)
may be indicated.
Definitive hormonal treatment is indicated in any T with the
Patients with comorbidities that contraindicate surgery or
radiotherapy. Patients with PSA greater than 50 ng / ml. If there
is humoral progression after: Radiation therapy when the PSA is
greater than 7. Prostatectomy when the PSA is greater than 4. In
Stages T1b-T1c- T2 in patients older than 80 years with less than
10 years of life expectancy, who do not accept control or have
symptoms as a consequence of their prostate disease. In T3 after
reassessing the local response to neoadjuvant treatment or in
those over 80 years of age. Stage T4 or Stage N1-2-3 or M1.
Prostate cancer constitutes the paradigm of the tumor in
which the dependence of hormonal stimulation (androgens) on tumor progression was identified decades ago. Hence, androgen
deprivation has been the focus of treatment for metastatic disease,
as well as for certain non-disseminated disease conditions (e.g.
Two clinical situations are identified in relation to hormone
therapy, which we will consider in order to evaluate the
a) Sensitive to castration
b) Castration resistant
The use of the so-called “complete androgen blockade”, the
association of LHRH analogues + antiandrogens, is common. More
appropriately, it should be called “dual androgen blockade” since
it does not know the adrenal pathway for androgen synthesis, thus
not being a “complete block”. A meta-analysis that has evaluated
patients treated with the combination of analogs + antiandrogens
vs analogues in monotherapy, has not shown differences between
the two treatments at 24 months. At 60 months, a modest increase
in survival has been observed in the group treated with the
combined blockade. For this reason, depending on the impact on
survival and toxicity secondary to the combination, the suggestion
would be that the treatment be only combined in the first month,
to avoid the flare secondary to the initial increase in androgens
by the analogues, and then suspend them , continuing only with
the analog. For situations that require a rapid antiandrogenic
effect, e.g. spinal compression, surgical castration is the preferred
procedure, a procedure that achieves castration plasma
testosterone levels in the shortest possible time.
Optionally, the analog (agonist) can be replaced by a pure
antagonist of the releasing factors, which has the peculiarity
of inducing castration plasma testosterone levels within 48 to
72 hours. As it does not produce flare, it does not need to be
associated with an antiandrogen. Faced with the progression to
initial hormonal treatment, subsequent hormonal manipulations
are usually carried out depending on the previous therapeutic
decision, e.g. If only LHRH analog, added antiandrogen
If dual block, try Antiandrogen Suppression (SAA) Consider
estrogen therapy in patients without cardiovascular risk.
Eventually consider Ketoconazole. In practice, numerous
hormonal manipulations are carried out, some with a certain logic,
others lacking it, which lead to the deterioration of the patient and
the impossibility of exposure to other treatments due to impaired
Performance Status (PS). Many times, these manipulations delay
the diagnosis that the patient has evolved to a disease resistant to
Three studies have been published that include early
chemotherapy with DOCETAXEL associated with HORMONE
THERAPY. The first of them was GETUF GA 15 in metastatic patients,
although negative, since it did not meet its Primary Objective (OP)
of Overall Survival (OS): at 82.9 months of follow-up it showed
OS: 60.9 vs 46.5 months (HR = 0.90 P = 0.44). However, it did
modify the Secondary Objectives (OS): Progression Free Survival
(PFS) both Clinical (23.5 vs 15.4 months), and by PSA (22.9 vs
12.9 months) showed benefit for the arm of the combination of
deprivation therapy. androgens (ADT) with Docetaxel.
The second study, CHAARTED, also carried out in metastatic
patients, showed a clear benefit in OS in favor of the arm of the
combination with Docetaxel (57.6 vs 44 months), identifying
a greater benefit in the group of patients with high volume of
disease. High volume is defined in this study as visceral disease
and / or 4 or more bone lesions, with at least one of them in an
extra axial location. A 17-month benefit was observed in OS, the
results for the low-volume group having not yet been achieved.
The third and last clinical trial confirming the incorporation of
Docetaxel in this group of patients is STAMPEDE. In 61% they were
M1 and 39% M0 unlike the previous ones, which included only M1
patients. It showed a 24% decrease in the risk of death, with a
difference in OS of 77 vs 67 months in favor of the combined arm.
There was also a 38% decrease in the risk of relapse, evidenced by
a difference of 37 vs. 21 months in PFS. The Mean Survival (SM)
was 60 vs. 45 months in favor of the combination of Docetaxel
plus HT with a 5-year survival of 50 vs. 39%.
In an analysis by Dr. Claire Vale’s group of all these studies
s clearly an improvement in OS was demonstrated in metastatic
patients, with a benefit of 10% (an increase from 40 to 50%) at
4 years with a prolongation of PFS of 15% (from 80 to 65%) at 4
years on the other hand, in the group of patients M0 the benefit
in OS it was only 5% (from 80 to 85%) at 4 years, as well as a
prolongation in PFS of 8% (70 to 62%). Given these results, in
castration-sensitive metastatic patients with visceral disease
and high-volume bone involvement, as defined above, adding
Docetaxel to HT treatment at the start of treatment should be
considered as STANDARD. At the moment, the use of Docetaxel
plus ADT in the group of non-metastatic patients cannot be
endorsed, requiring greater evidence of benefit as well as longerterm
We consider two definitions in this situation, that of the
Prostate Cancer Working Group 2 (PCWG2) and that of the
European Association of Urology, (USA)
A.1 PCWG2, biochemical failure (PSA only), in a patient with
serum testosterone levels compatible with castration, namely: a.
Increase> 2 ng / ml, above nadir
b. at least 25% above it
c. confirmed by a second determination after 3 weeks
A.2 USA, defines this condition as the one that occurs in a
to. Serum testosterone levels <50 ng / dl or <1/7 nmol / l
b. Presenting 3 consecutive elevations of PSA separated by 1
week, resulting in 2 elevations ≥ 50% above nadir, with PSA> 2
ng / ml
c. The SAA must have been tried which will be 4 weeks for
Flutamide and 6 weeks for Bicalutamide
d. PSA progression despite consecutive standard hormonal
and. Appearance of at least 2 new lesions in Bone Gamma
or in soft tissues, measured by RECIST1 (≥2 cm).
To synthesize then, once the biochemical and / or clinical
progression has been verified as defined above, one must:
Confirm the castration status: determination of plasma
Confirmed the same, the Suppression of Antiandrogen should
1 Response Evaluation Criteria in Solid Tumors.
Different situations should be considered when
a) Exclusive biochemical failure
b) Evidence of metastatic disease (M1)
c) Clinical condition of patient M1, asymptomatic,
minimally symptomatic or symptomatic
d) Performance Status (PS)
Previous treatment to which the patient was subjected
(Chemotherapy yes vs no)
Associating these different variables, we have the following
a) Asymptomatic or minimally symptomatic patient,
without prior chemotherapy
b) Symptomatic patient, with good PS, without previous
c) Symptomatic patient with bad PS, without previous
chemotherapy d. Symptomatic patient, with good PS and previous
Docetaxel and symptomatic patient, with bad PS and previous
These different situations will be conditioning factors of
the proposals to the patient. They could range between specific
therapeutic interventions and palliative care. First line of
treatment (note that chemotherapy or hormone therapy but lines
of treatment). Before discussing the different treatment options
available for CRPC patients, it should be clarified that all these new
drugs have been tested in patients with evidence of metastatic
disease, generally asymptomatic or minimally symptomatic, and
with PS 0-2.
These do not constitute minor data when defining the
particular treatment for each patient, since they delimit the
population in which the therapeutic benefit is demonstrated.
Likewise, it should be clear that those patients with CRPC with
exclusive biochemical failure are therefore not candidates for
these therapeutic manipulations. In these particular cases, it is
recommended to continue hypothalamic pituitary inhibition by
LH RH analogs or antagonists, but not to introduce any of these
medications in the absence of documentation of metastatic
Docetaxel + Prednisone
It was the first chemotherapy association that had an impact
on progression-free survival (PFS). That patient with dominant
visceral disease, symptomatic and with good PS, constitutes the
ideal patient, since chemotherapy offers the responding patient
a possibility of rapid response. As is widely known, in recent
years the results of studies in this patient population have been
published, which have significantly expanded the therapeutic
armamentarium. These options are discussed below.
Abiraterone 1000 mg + prednisone + LHRH analog
Abiraterone is an inhibitor of adrenal steroid production,
acting at the level of the CYP17 complex, which not only affects
androgen synthesis, but also that of mineralocorticoids and
glucocorticoids, which requires a knowledge of the functioning of
this hormonal axis in order to maintain its balance and prevent
This drug has shown utility both in patients who fail Docetaxel
and in those who have not received it, and it has approval from
the regulatory authorities in both scenarios (M1 patients, pre and
post Docetaxel). The COUA 301 and 302 studies have shown this,
presenting prolongation of progression-free survival (PFS) when
compared with placebo, the impact on OS is affected given the
high rate of Cross Over.
The addition of Prednisone reduces the incidence of them. The
decision must be made based on: Comorbidities that limit the use
of one or another medication Condition of the disease, the patient
with a great burden of disease, particularly visceral, possibly from
maintaining an adequate PS benefits more from chemotherapy.
Enzalutamide, a potent antiandrogen with a high affinity for
the Receptor Androgenic, it has shown efficacy in the pre and
post Docetaxel scenarios. The results of the PREVAIL trial have
recently been published, in which the drug has been studied
in chemotherapy-naïve patients. In them, it has been shown
to be highly effective, prolonging the parameters under study
significantly. The risk of seizures should be considered, which,
although it has been significantly reduced with the recommended
dose of 160mg, could be increased in patients with a history of
epilepsy or cerebrovascular accident (CVA).
C. Castration resistant patient progressing to first line of
treatment, depending on the first line, the options would be:
Docetaxel + Prednisone, or Abiraterone or Enzalutamide or
Cabazitaxel The AFFIRM study demonstrated the impact of
Enzalutamide on PFS when compared to placebo and formed the
basis for the registration of the drug, leading to an early closure in
the interim analysis. Cabazitaxel is a taxane that has proven useful
in patients progressed to Docetaxel (TROPIC trial). The patient’s
situation, age, and comorbidities should be considered for this
indication, given his hematological toxicity that has required the
addition of granulocyte-macrophage colony-stimulating factors. It
is an option for those who are able to receive it.
As can be seen, in the decision regarding a patient who has
progressed to the first line in the situation of CRPC, several
factors must be taken into account. It is a decision in which
both chemotherapy and hormonal therapy options should be
considered, with clinical judgment and the notion of a possible
therapeutic sequencing being important. The best therapeutic
sequence is not clearly defined at the moment. However, it
would appear that direct Abiraterone sequencing followed by
Enzalutamide or vice versa would not offer major advantages.
Therefore, the option of chemotherapy with Docetaxel after
the failure of one of these molecules in CRPC would perhaps be
Bone Antiresorptive Treatment
Prostate cancer is associated with high frequency with the
occurrence of bone metastases, which exposes these patients
to the risk of secondary complications, pain, fractures, spinal
compression. Also, the age of the patients and the antiadrogenic
treatments increase the risk of osteopenia and osteoporosis.
Bone mineral density is not studied as rigorously in males as in
females, however, in the face of these risks it must be considered.
Bone antiresorptive treatment has modified the natural history of
those patients with bone metastases from various tumors, and it
must be borne in mind as a treatment associated with the specific
Zoledronic Acid has been shown to induce a prolongation of
the appearance of related bone events, such as a decrease in the
incidence of fractures and spinal cord compression, in prostate
cancer in particular.
We currently have Denosumab, an anti RANKL2 antibody,
which has the advantage of being able to be used in patients
with impaired renal function, which is usually limiting in the
case of zoledronic acid and can be administered subcutaneously.
2 Receptor Activator for Nuclear Factor κ B Ligand. In both
cases, calcium, kidney function, and vitamin D levels should be
monitored, and the risk of osteonecrosis of the jaw should be
monitored, which has been reported with both drugs.
Radioisotopes have also been used in these situations.
Strontium and Samarium, although they have been associated
with transient subjective improvements, have been myelotoxic
and this has limited their use.
Radium 223, (Alpharadim), is an alpha particle emitting
isotope, which produces a break at the level of the DNA double
helix with minimal to exposure of surrounding tissues. This
makes the myelotoxicity profile significantly different from
previously known isotopes. In a phase III trial (ALSYMPCA), in
symptomatic patients with or without prior chemotherapy, not
only a prolongation of the appearance of bone-related events
and an improvement in quality of life has been observed, but also
a prolongation of the mean survival of the patients treated as
opposed to those receiving placebo.
This suggests not only an effect on bone metabolism but also
a specific effect on disease. Radium 223 is particularly indicated
in patients with castration-resistant prostate cancer, symptomatic
with exclusive bone disease, both in those who maintain a good
PS, as well as in those with deterioration of the same attributable
to the disease.
Although specific treatment constitutes the core of the
treatment of patients with advanced prostate cancer, we must
always bear in mind that palliative care must run in parallel with
specific treatment. The palliation of the symptoms of our patients
is fundamental, resulting in an improvement in their quality of
life, and in the face of a deterioration of the PS and the decision to
discontinue specific treatment, palliative care emerges as central,
in patients suffering from a disease that Despite their advanced
state they can survive for a long time, and this time must be of the
best possible quality.
Current controversies about hormone therapy
Not all studies agree on the many issues related to hormone
therapy, such as the best time to start or stop therapy and the
best way to give it. Studies are underway that are looking at these
issues. Some of these issues are discussed below.
Early Stage Cancer Treatment
There is research proposing hormone therapy rather than
observation or active surveillance in men with early-stage prostate
cancer who do not want to have surgery or radiation. Studies have
not found that these ho Others live longer than those who only
receive treatment when the cancer progresses or when symptoms
develop. Because of this, hormone treatment is generally not
recommended for early-stage prostate cancer.
Early treatment or late treatment
For men who need (or will need in the future) hormone
therapy, such as men whose PSA levels are increased after surgery
or radiation, or men with advanced prostate cancer who do not yet
have symptoms, not always it is known when to start hormonal
treatment. Some studies suggest that hormone therapy works
best if it is started as soon as possible, even if the man feels fine
and has no symptoms. Some studies have shown that hormone
treatment can slow down the disease and perhaps even help men
However, not everyone agrees with this method. More
evidence is expected to show that there are benefits. They believe
that treatment should not be started until a man has symptoms
of cancer, due to the side effects of hormone therapy and the
possibility that the cancer will sooner become resistant to therapy.
This issue is still under study.
Intermittent hormone therapy versus continuous
Most prostate cancers treated with hormone therapy over
a period of months or years become resistant to this treatment.
Some studies suggest that constant androgen suppression may
not be necessary, so they recommend intermittent treatment. The
intention is that the interruption of androgen suppression will
also provide men with a break from side effects such as decreased
energy, sexual problems, and hot flashes.
In a type of intermittent hormone therapy, treatment is
stopped when the PSA in the blood drops to a very low level. If
the PSA level begins to rise, the drugs are started again. Another
method of intermittent therapy uses hormone therapy for fixed
periods of time, for example it is given for 6 months and is off for
the next 6 months.
At this time, it is not known what benefits this approach has
over continuous hormone therapy. Some studies have found that
continuous therapy can help men live longer, but other studies
have found no such difference.
Combined androgen blockade
There are studies that treat patients with androgen
deprivation (orchiectomy or LHRH agonist or antagonist) and an
antiandrogen. Some studies have suggested that this may be more
helpful than androgen deprivation alone, although other studies
do not agree with this. There is not enough evidence to indicate
that this combination therapy is better than starting with a single
drug to treat prostate cancer that has spread to other parts of the
Triple androgen blockade
Studies have suggested adding an additional step to
combination therapy by adding a drug called a 5-alpha reductase
inhibitor, either finasteride (Proscar) or dutasteride (Avodart), to
the combined androgen blockade. At present, there is very little
evidence to support the use of this triple androgen blockade.
Castration-sensitive, castration-resistant, and
hormone-refractory prostate cancer
These terms are sometimes used to describe how well a
patient’s cancer responds to hormone therapy.
a) Castration-sensitive prostate cancer means that the
cancer is being controlled by keeping testosterone levels as low
as they would be expected if the testicles had been removed
(referred to as the castration level). Levels can be maintained at
this low amount by an orchiectomy or by administering either an
LHRH agonist or antagonist.
b) Castration-resistant prostate cancer means that the
cancer continues to grow even when testosterone levels are as
low as would be expected to be at or below the castration level.
Some of these cancers may benefit from other forms of hormone
therapy, such as abiraterone or some of the newer antiandrogens.
c) Hormone-refractory prostate cancer refers to prostate
cancer that no longer benefits from any type of hormone therapy,
including newer medications.
About 30% of patients with prostate cancer present as
“D” stages of disease, that is, with metastases at the time of
diagnosis, while 20-25% of patients develop distant metastases
during tumor evolution. The standard of care for disseminated
prostate cancer is androgen suppression hormone therapy. The
treatment obtains a high percentage of remissions (between
70-80%), although in a period of 12 to 18 months the tumor
evolves towards a hormone-resistant phase with a survival that
does not usually exceed 6-12 months. In this situation, secondline
hormonal treatments with estrogens, aminoglutethimide,
ketoconazole, progestogens, corticosteroids or antiandrogens
obtain a response rate of less than 20% with a duration of 4-6
months. Traditionally, prostate cancer has been considered a
chemo resistant tumor. In the 1980s, various cytostatics showed
low activity in patients with HRPC, with an objective response rate
of less than 10% and a mean survival between 6 and 12 months,
similar to that obtained with supportive treatments. However, in
recent years the treatment of hormone-resistant prostate cancer
has undergone profound changes.
The systematic determination of PSA levels has allowed
the diagnosis of HRPC in earlier stages, in patients with a better
performance status, which can facilitate the efficacy and tolerance
of chemotherapy treatment. Likewise, given the absence of
measurable tumor lesions in the majority of patients with
HRPC, the decrease in PSA levels has been used as a marker of
chemotherapy efficacy, despite the fact that various evidences
indicate that variations in levels PSA levels do not always correlate
with the course of the disease.
Various cytostatic have shown some activity in patients
with HRPC, especially when the decrease in PSA has been used
as a response marker. Among the most commonly used classic
cytostatic are the vinca alkaloids (vinblastine, vinorelbine),
cyclophosphamide and the anthracyclines (adriamycin,
epirubicin, mitoxantrone). The combination of mitoxantrone
with corticosteroids has been widely used in patients with HRPC
due to the results of two randomized studies published in the
second half of the last decade. In both studies, the combination
of mitoxantrone with prednisone or hydrocortisone showed a
significant benefit in the palliation of symptoms and at the PSA
level, although without improving survival, compared to treatment
with corticosteroids. A third randomized study confirms that
the mean survival in patients treated with mitoxantrone and
prednisone does not exceed 12 months, as in previous studies.
Until now, the combination of mitoxantrone and corticosteroids
has been considered the standard treatment in patients with
Single agent estramustine phosphate has low activity in HRPC,
however, its action on microtubules makes its activity synergistic
with other cytostatic such as vinca alkaloids, etoposide and
taxanes. The combination of these cytostatic with estramustine
phosphate has shown a high percentage of responses by PSA,
higher than 50% in many of the published studies, with a high
percentage of responses in patients with measurable lesions and a
mean survival greater than 12 months in some of them. However,
these data have been obtained in phase II studies, sometimes with
a small number of patients and, therefore, can be questionable.
In recent years, the activity of taxanes (paclitaxel and
docetaxel) in the CPHR has attracted special attention. Studies
in prostate cancer cell lines have demonstrated the ability of
paclitaxel to reverse the resistance induced by overexpression of
the bcl-2 gene. In clinical practice, the combination of paclitaxel
with other drugs, especially estramustine phosphate, has shown
relevant activity with a PSA response rate greater than 50% and a
mean survival between 13 and 17 months.
Recently, several studies have analyzed the activity of
docetaxel in regimens of administration every 21 days or weekly.
Both schemes show a high percentage of responses by PSA. In the
phase II study by Savaresse et al., 47 patients with HRPC were
treated with docetaxel (70mg/m2 every 21 days), estramustine,
and hydrocortisone. The PSA response rate was 69%, with a
measurable lesion response rate of 50% (12 of 24 patients) and
a mean survival of 20 months. The combination of estramustine
with docetaxel appears to increase the efficacy of docetaxel. In a
recent randomized phase II study, the combination of docetaxel
/ estramustine shows a benefit in terms of PSA responses and
progression-free survival compared to treatment with docetaxel,
although the impact it may have on survival has not been
The benefit of docetaxel-based regimens has been confirmed
in two recent phase III studies published in October 2004, which
show that docetaxel regimens provide significant benefit in
survival compared to the standard regimen with mitoxantrone
and prednisone. In the Southwest Oncology Group study 9916,
674 patients with metastatic HRPC were randomized to receive
docetaxel (60mg / m2 day 2), and estramustine phosphate (280mg
po, days 1-5) or mitoxantrone (12mg / m2 every 21 days) and
prednisone (5mg PO daily). After the first cycle of treatment, the
doses of docetaxel and mitoxantrone were increased to 70mg / m2
and 14mg / m2 in patients who did not present grade 3-4 toxicity.
90% of the patients had a good general condition (PS 0-1), and in
around 20% of cases, tumor progression was established solely
by increases in PSA.
In patients treated with docetaxel / estramustine, a significant
increase in episodes of neutropenic fever, cardiovascular toxicity,
nausea, metabolic disturbances and neurotoxicity was observed.
The biochemical response rate for PSA was significantly higher in
the docetaxel scheme (50% vs. 27%, p <0.0001). Progression-free
survival was 6.3 months in the docetaxel arm compared to 3.2
months in the mitoxantrone regimen (p <0.001). Median survival
was 17.5 months in patients treated with docetaxel / estramustine
and 15.6 months in patients treated with mitoxantrone /
prednisone (p = 0.02).
In the second TAX 327 study, 1006 patients with metastatic
HRPC were randomized to receive docetaxel 75 mg / m2 every 21
days vs. docetaxel weekly (30mg /m2 weekly in cycles of 5 doses
every 6 weeks) vs. the standard mitoxantrone regimen (12mg/m2
every 21 days). In the 3 schemes prednisone was administered
at a dose of 5 mg 2 x day. The duration of treatment in the 3 arms
was 30 weeks
The characteristics of the patients were similar to the SWOG
9916 study, more than 90% of patients received 2 or more
hormonal treatments. The most relevant toxicity was grade 3-4
neutropenia present in 32%, 1.5%, and 22% of patients treated
with docetaxel every 3 weeks, weekly docetaxel, and mitoxantrone,
respectively. Non-hematological toxicity was significantly higher
in the patients treated with docetaxel, although the incidence of
grade 3-4 toxicity was less than 5% in the 3 treatment arms.
The PSA response rate was significantly higher in the
docetaxel-treated patients, although the objective response rate in
measurable lesions was similar with all three regimens. Especially
relevant is the fact of the significant improvement in pain control,
and in the quality of life observed in the patients treated with the
two schemes with docetaxel. The mean survival of patients with
docetaxel was significantly higher than that observed in patients
treated with mitoxantrone (p = 0.03, Hazard Ratio: 0.83). These
differences were especially significant with the docetaxel scheme
every 21 weeks (18.9 vs 16.5 months, p = 0.009), on the contrary,
the differences with weekly docetaxel did not reach statistical
significance (17.4 vs 16.5 months, p = 0.36). Patients with visceral
involvement, anemia, elevated alkaline phosphatase levels, and
undifferentiated tumors (Gleason 8-10) had a worse prognosis.
These studies demonstrate that docetaxel-based regimens
significantly improve survival over mitoxantrone / prednisone
and should be considered the standard of care in advanced HRPC.
The differences are statistically significant despite the fact that
the mean survival obtained in these studies with mitoxantrone /
prednisone (around 16 months) is higher than that obtained in
the previous randomized studies (12 months). This fact may be
due to the fact that a significant percentage of patients treated
with mitoxantrone received docetaxel after progression (20%
of patients in the TAX 327 study), also the characteristics of
the patients may be more unfavorable in previous studies, for
example, the mean baseline PSA levels were higher in the Kantoff
et al study compared to current studies. Regarding toxicity,
although the schemes with docetaxel are associated with a higher
incidence of adverse effects, the percentages of grade 3-4 toxicity
are acceptable. Other points of interest raised by these studies are:
The weekly docetaxel regimen, despite significantly increasing
the percentage of responses by PSA, does not improve survival
compared to mitoxantrone / prednisone treatment and, therefore,
cannot be considered an alternative treatment to the docetaxel
regimen every 21 days, despite to present a better hematological
Treatment with estramustine does not appear to provide a
benefit to the combination with docetaxel over treatment with
prednisone (mean survival of 17.6 months with docetaxel /
estramustine and 18.9 months with docetaxel / prednisone).
This fact is especially relevant, if one takes into account that
patients treated with estramustine have a 7% risk of presenting
thromboembolic processes. Therefore, it is necessary to seek
more active treatments to combine with docetaxel).
Today, men with prostate cancers that continue to progress
despite initial hormone therapy have many more treatment
options than they did a few years ago. If an antiandrogen was not
part of the initial hormone therapy, it is often added at this time.
In case the patient is receiving an antiandrogen, but the cancer
continues to grow, stopping the antiandrogen (while continuing
other hormonal treatments) sometimes seems to help.
Other forms of hormone therapy may also be helpful for a
time, especially if the cancer is causing few or no symptoms. These
include: abiraterone, enzalutamide, apalutamide, darolutamide,
ketoconazole, estrogens (female hormones), and corticosteroids.
The prostate cancer vaccine, sipuleucel-T (Provenge), is another
option for men whose cancer is causing few or no symptoms. This
treatment may not lower PSA levels, but it can often help patients
For cancers that are no longer responding to initial hormone
therapy and that are causing symptoms, there may be several
options available. Chemotherapy with the drug docetaxel
(Taxotere) is often the first choice because it has been shown to
help men live longer as well as reduce pain. If docetaxel does not
work well or stops working, other chemotherapy drugs, such as
cabazitaxel may help. Pembrolizumab immunotherapy may also
be an option after chemotherapy if the cancer is MSI-H or dMMR.
Another option may be a different type of hormone therapy, such
as abiraterone or enzalutamide or apalutamide (if they have not
already been treated). Bisphosphonates or denosumab can often
help if the cancer has spread to the bones. These drugs can reduce
pain and even slow cancer growth in many men. Other medications
and methods can also help keep pain and other symptoms under
control. External radiation therapy can help treat bone pain if it
is only present in a few places. Radiopharmaceuticals can often
reduce pain if it is more widespread, and they can also slow
Be sure to tell your doctor and your healthcare team if you
experience pain caused by prostate cancer.
Several promising new drugs are currently being tested against
prostate cancer, including vaccines, monoclonal antibodies, and
other newer types of drugs. Because the ability to treat hormonerefractory
prostate cancer is not yet effective enough, men are
encouraged to participate in clinical trials to explore new options.
Active surveillance for prostate cancer
Most men diagnosed with prostate cancer have localized
cancer, meaning that the cancer has not spread outside the
prostate. Some men with localized prostate cancer choose active
surveillance, which allows them to avoid or delay having surgery
or radiation. Active surveillance is an option for men with a cancer
that is very unlikely to progress or metastasize. The tests will
indicate if the cancer is likely to be aggressive.
With localized prostate cancer Low-risk cancer has a very low
chance of advancing immediately. These men may opt for active
surveillance. This means that regular check-ups and testing will
be needed to see if it progresses. This option allows a man to delay
surgery or radiation therapy, often for many years. If the cancer
grows very slowly, treatment may never be needed. Intermediaterisk
cancer is more likely to grow. Some men with this type of
cancer may be able to choose active surveillance. Others may have
to choose surgery or radiation therapy. High-risk cancer has a
high chance of metastasizing. Men with high-risk cancer may have
to choose between surgery or radiation. Whether or not active
surveillance is a good option is something that will usually have to
be discussed with the oncologist.
Factors to Consider (Risk Factors)
a) Life expectancy.
b) The stage and Gleason score of your cancer
c) General health status.
d) Possible side affects you might have from other
e) Personal preferences should be part of this decision.
With active surveillance, clinical follow-up is done. During this
time, you will be monitored and tested, such as PSA tests, digital
rectal exam and prostate biopsies. It may seem strange to have
cancer and not have surgery to remove it or not have radiation
therapy to remove the cancer. But, unlike many other types of
cancer, most prostate cancers grow very slowly. Slow-growing
prostate cancer usually does not cause symptoms. Therefore, it
is possible to have prostate cancer for years without knowing it.
Prostate cancer treatments such as surgery and radiation have
serious side effects. These side effects include bladder, bowel
and erection problems. With active surveillance, men can wait
before starting other treatments. Some men will never need more
treatment. And others may delay treatment until evidence shows
that the cancer is growing faster.
Regular checkups will show if the cancer is progressing. And
if it does, the cancer can still be treated in the early stages, when
treatments are most successful.
What to expect after treatment?
Active surveillance sometimes continues for years. In other
cases, there comes a time when evidence indicates that the cancer
is growing and needs to be treated.
Why it is done
Prostate cancer is usually a slow-growing type of cancer.
About 12 out of every 100 men in Argentina will have prostate
cancer. But most men who are diagnosed with prostate cancer do
not die from it.
Men with localized prostate cancer who have a low probability
of their cancer spreading can opt for active surveillance. One study
compared active observation (a wait-and-see program like active
surveillance), surgery, and radiation in men with localized prostate
cancer and found that the risk of dying was very low and about the
same, regardless of the alternative the men chose. Another study
examined men with low-risk localized prostate cancer (and some
men with intermediate-risk prostate cancer) and found that At 5
years, approximately 76 of every 100 men were not treated and
were still on active surveillance. At 10 years, approximately 64
men out of 100 did not receive treatment and were still on active
surveillance. At age 15, approximately 55 of every 100 men were
not treated and were still on active surveillance.
Prostate cancer is likely to grow during active surveillance.
If this happens, treatment, such as surgery or radiation, must
be indicated. If the patient chooses active surveillance, it is very
important to follow the schedule of tests and exams. Regular
checkups will increase the chances of knowing right away if the
prostate cancer grows. That way, the cancer can still be treated in
the early stages, when treatments are most successful.
At present, regimens based on docetaxel plus enzalutamide or
with abiraterone are the gold standard in advanced HRPC. These
regimens obtain around 50% responses by PSA, a progressionfree
survival of 6 months, and a mean survival of 18 months.
The positive impact on survival of the docetaxel regimens is
accompanied by an improvement in pain control and in the
quality of life of the patients compared to the classical treatment
with mitoxantrone / prednisone.
New cytostatic (epothilones) have shown activity in HRPC,
even in patients previously treated with taxanes.
New agents that act on specific targets show promising
activity, especially in combination with cytostatic.
Better knowledge of the genetic alterations involved in the
development of hormone-resistant prostate cancer may allow the
selection of the most appropriate treatment for each patient.
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