Prostate Cancer News of interest for October, 2018
Contents
The Next IPCSG Meeting
Saturday October 15, 2018 10:00 AM
Member Panel Personal
PCa Stories
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Nutrition, ADT, and metastatic prostate cancer
Posted on October 8, 2018
Most men who are taking androgen deprivation therapy
(ADT) for metastatic prostate cancer feel the need to “do something” about
their diet in order to (a) further help to control the risk for progression of
their cancer and (b) help to cope with the side effects of ADT.
Another paper just published in Prostate Cancer and
Prostatic Diseases this month is a review by Barnes et al. on whether current
nutrition care guidelines for men with prostate cancer who are being treated
with ADT are really based on good enough evidence.
The authors claim to have been able to find just 16
articles on this topic that met the inclusion criteria for their review, and
they summarize their findings as follows:
·
Each of the 16 articles offered distinct sets of
dietary interventions designed to manage the side effects of ADT.
·
12/16 articles combined nutritional guidelines
with physical activity and/or medications and/or counseling.
·
4/16 articles dealt exclusively with the impacts
of diet alone, and among these four articles
o Three
articles measured changes to participants’ dietary intake and influence on ADT
side effects.
o One
article showed daily caffeinated beverages improved cancer-related fatigue.
o Two
articles showed no impact of isoflavone supplementation on hot flashes, quality
of life, body mass index, or blood lipids.
·
Among the 16 articles altogether
o Dietary
intake and compliance was poorly reported (and thus provided limited knowledge
of acceptability and feasibility for dietary interventions).
o Information
on the nutrition care practices and views of clinicians treating men for
prostate cancer is limited.
o No
articles measured the impact of diet on long-term side effects of ADT.
o The
methodological quality of the papers ranged from weak to strong.
Barnes et al. conclude that:
·
Current evidence for dietary interventions to
mitigate ADT side effects is limited. Further investigations are warranted to
explore the impact of changes in dietary intake on ADT side effects before
practice guidelines can be considered.
We have considerable sympathy with the findings of
Barnes et al. In general, our knowledge of what really “works” from a dietary
and a nutritional perspective to optimize the quality of life of men with
prostate cancer and of men with prostate cancer who are on ADT is poor.
While we know what is a really bad idea (e.g., diets
high in red meat and carbohydrates and animal fats) and we know that some men
believe they do really well on diets that are almost entirely vegetarian or
vegan, the question of how well any of these diets actually work for large
numbers of men has yet to be answered in any really well conducted studies.
Thus our advice to most men at the present time
generally takes three forms:
·
Eat a well balanced diet that is significantly
lower in red meat, carbohydrates, animal fats, and sugars than the average US
diet today.
·
Eat more cruciferous vegetables (things like
broccoli, cauliflower, cabbage, and brussels sprouts), nuts, and roughage.
·
Exercise regularly and work up a good sweat if
you can when you do.
We know these things are good for the heart and for
other bodily functions too, and there is plenty of evidence to suggest they are
also good for people with cancers of many types.
However, it would be really nice to know if specific
diets and supplements had real, definable benefits for men on ADT. Many men
swear by the value of soybean-based products as a way to down-grade the impact
of ADT on hot flashes, but whether this is really true for most men — based on
a well-controlled and randomized trial — remains utterly unknown.
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Personalized Medicine in Prostate Cancer: Now More Precise
Raoul S.
Concepcion, MD, FACS
Over
the past decade, we have witnessed an explosion of molecular testing in the
urology world that will help us better diagnose and manage prostate cancer
across the spectrum of the disease. All of us recognize that we have fallen
behind our colleagues who treat other tumor types and for whom routine lab and
tissue testing is the requirement or norm for optimal therapeutic choices.
However, we are making progress.
We
know that prostate cancer is an endocrine disease and the androgen receptor
(AR) plays a major role in disease progression, even when serum testosterone is
at castration levels of the hormone. Androgen deprivation therapy (ADT)
continues to be the foundation of treatment on which all other oncolytics are
layered as the patient begins to progress. However, treatment pressure
selection and tumor heterogeneity will result in cellular mutagenesis that
makes ultimately eradicating the disease a daunting task. In patients with
metastatic castration resistant prostate cancer, a number of these mutations,
which will inevitably confer resistance to therapy, have been discovered. For
example, prostate cancer cells that have been long exposed to ADT and are now
starved of their fuel for survival can produce their own ligands to survive.
This is comparable to a car that could produce its own gasoline (or
electricity)—very nice if you are the automobile owner—but the reality is not
so desirable for the patient with cancer. AR, the very target of ADT, can
undergo genetic alterations that will result in downstream changes leading to
resistance and cell survival.
Fortunately,
we are in the early stages of developing biomolecular markers that will help
the clinician to choose better therapies to try to stay ahead of these
mutations. The ability to measure circulating tumor cells has led to the
development and marketing of commercial assays to detect these aberrations—AR
splice variants—that may be predictive of what agent should be used next in the
treatment paradigm. In addition, patients who harbor homozygous mutations of
inherited DNA repair genes, most notably BRCA2, may in fact respond to PARP
inhibition therapy. Also, DNA sequencing to test for these gene mutations can
now be clinically implemented in the appropriate patient.
Thus,
just as it is difficult to keep track of all the FDA-approved therapies, their
mechanisms of action, adverse event profiles, and current approval status, we
are additionally challenged to stay up-to-date with the molecular tests that
may ultimately be required to determine when and where to use these drugs in
the appropriate sequence for each patient. The vernacular commonly used in the
press is the “era of personalized medicine.” I will argue that the art of
medicine has always been personalized. We as providers do not adhere to a
single agent, from an antibiotic to an antihypertensive to an oncolytic, for
all patients. All of us consider the patient’s medical history and
comorbidities and a host of other factors to best determine which agent to
prescribe in hopes of achieving the best outcome. Now, given the complexity in
understanding these malignancies and their ability to undergo evolutionary
mutations to survive, we must clearly understand how to accurately test and
target these dynamics to stay ahead of the changing tumor environment. Personalized
yet ever more precise at the tumor level—precision medicine. This is how all of
us will need to practice moving forward to continue making strides in advancing
cancer care.
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What to Expect When Active Surveillance Leads to Prostatectomy | Medpage Today: High-risk features in 39% of prostate specimens at surgery
Oncology/Hematology
> Prostate Cancer
by Charles Bankhead, Senior Associate
Editor, MedPage Today
September 21, 2018
A
high proportion of men who entered active surveillance for early prostate
cancer had one or more high-risk disease characteristics when they subsequently
had radical prostatectomy, a Swedish study showed.
Medical
records showed that 52 of 132 men had at least one adverse pathology feature at
radical prostatectomy. All the men initially opted for active surveillance, and
the median time from enrollment to surgery was 1.9 years.
Adverse
pathology findings included Gleason score >3 + 4, extraprostatic extension,
positive surgical margins, seminal vesicle invasion, and lymph node
involvement, as reported in the Journal of Urology.
"Our
findings can be used to counsel patients on AS (active surveillance) regarding
what to expect in those who progression during surveillance and undergo
deferred radical prostatectomy, as 85% of the cohort had objective signs of progression
triggering treatment, including upgrading or increased cancer volume or PSA
(prostate-specific antigen)," Rebecka Arnsrud Godtman, MD, of the
University of Goteborg and Sahlgrenska University Hospital, and co-authors
wrote.
"The
results underscore the need to determine better methods of risk classification
and identify progression during AS to select the best treatment strategy for
each individual patient at each phase of the disease."
Another
study in the same issue of the journal showed positive results with a minimally
invasive technique that dramatically reduced the frequency of progression to
radical prostatectomy among men on active surveillance. The 2-year rate of
conversion was 7% among men who had tissue ablation with vascular targeted phototherapy
(VTP) prior to beginning active surveillance versus 32% for those who had no
treatment prior to starting surveillance. At 4 years, the prostatectomy rates
were 24% in the VTP group and 53% in the surveillance group, reported Inderbir
Gill, MD, of the University of Southern California in Los Angeles, and
colleagues.
"Absolutely,"
Gill told MedPage Today when asked whether VTP might address the progression
issue observed in the Swedish study. "What we're showing is that
progression to radical prostatectomy occurs less often for [VTP] than with
active surveillance -- about 30% less often at 4 years.
"Conversion
to radical prostatectomy is primarily due to progression of the cancer,"
he added. "[VTP] arrests progression and decreases the need for radical
therapy up to 4 years now, and we already have 5-year data in the works."
The
findings added to those that Gill reported earlier this year at the American
Urological Association annual meeting. The findings came from a multicenter
randomized trial of the TOOKAD VTP system (Steba Biotech), which employs
low-level laser energy and light-activated padeliporfin di-potassium to induce
vascular necrosis and tissue ablation. Not yet available in the U.S., the
TOOKAD device has regulatory approval in Mexico, Israel, and most of the
European Union.
Although
a growing number of men with early prostate cancer opt for active surveillance,
half the patients eventually have radical therapy (surgery or definitive
radiation therapy). Combined with the proportion of men who have upfront
surgery or radiotherapy, about 70% of men still undergo definitive treatment
for early prostate cancer, despite the emphasis on active surveillance to
reduce overtreatment of low-risk disease, Gill noted.
Inherent
to the underlying rationale for active surveillance is the premise that the
time spent in surveillance will not jeopardize the chance of curing the
disease, Godtman and coauthors noted in their introduction. As a result,
meticulous selection and follow-up criteria are essential components of any
active surveillance program.
The
primary objectives of the Swedish study were to determine long-term outcomes of
men who deferred surgery in favor of active surveillance and to determine how
often tumors removed during radical prostatectomy are missed during interval
biopsies. Such information could inform development of active surveillance
programs and counseling patients about active surveillance for early prostate
cancer, the authors added.
Study
Details
The
analysis involved 132 men with screen-detected prostate cancer and who entered
active surveillance and subsequently underwent radical prostatectomy during
1995 through 2014. Follow-up in the cohort continued to May 2017. During active
surveillance, patients had PSA tests every 3 to 6 months and follow-up biopsies
every 2 to 4 years. Triggers for radical prostatectomy included rising PSA,
increased cancer grade or stage, and patient preference.
The
study population had a median age of 64 and a median PSA level of 4.1 ng/mL. At
diagnosis, 73 of the 132 men (55%) had very low-risk prostate cancer, 30% had
low-risk disease, and 14% had intermediate-risk disease characteristics.
The
cohort had a median interval from prostate cancer diagnosis to radical
prostatectomy of 1.9 years and median postoperative follow-up of 10.9 years.
Pathology reports for prostatectomy specimens showed that 39% of the patients
had at at least one adverse disease characteristic at surgery.
On
the basis of the pathologic features observed at surgery, the tumor was not
identified by the diagnostic biopsy in 29% of all 132 cases or by the repeat
biopsy that preceded radical prostatectomy in 21% of 105 cases, the authors
reported. The study population had a 10-year PSA relapse-free survival rate of
79.5%.
The
study by Godtman et al was supported by the Swedish Cancer Society. The authors
reported having no relevant relationships with industry.
The
study by Gill et al was supported by the National Cancer Institute, the
National Institute of Health Research (England), several private foundations,
and Steba Biotech. The authors reported having no relevant relationships with
industry.
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Prostate Cancer Paradigm Progresses, But Unanswered Questions Remain
Brandon
Scalea
Randy
F. Sweis, MD
Large
phase III studies, such as the CHAARTED and STAMPEDE trials, have helped to
significantly improved outcomes for men with prostate cancer, but unanswered
questions remain, including what role immunotherapy could play in the treatment
paradigm, said Randy F. Sweis, MD.
Long-term
survival data from CHAARTED demonstrated prolonged overall survival (OS)
benefit with docetaxel when added to androgen deprivation therapy (ADT) for
patients with high-volume metastatic hormone-sensitive prostate cancer. At a
median follow-up of 53.7 months, median OS was 57.6 months for the docetaxel/ADT
arm versus 47.2 months for ADT alone.1
The
STAMPEDE trial showed that in patients with locally advanced disease, ADT plus
abiraterone acetate (Zytiga) and prednisone was associated with higher rates of
OS and failure-free survival than ADT alone.2
Sweis,
an instructor of medicine at the University of Chicago, said ongoing trials are
testing immunotherapy in patients with prostate cancer. For example, the
CheckMate-9KD study will look at nivolumab (Opdivo) combined with either a PARP
inhibitor, androgen receptor therapy, or docetaxel in patients with metastatic
castration-resistant disease.
In
an interview during the 2018 OncLive® State of the Science Summit™, Sweis
discussed recent progress and next steps in the prostate cancer paradigm.
OncLive:
How has the treatment landscape of prostate cancer evolved in recent years?
Sweis:
Prostate cancer is an interesting disease because numerous therapies have been
FDA approved over the last few years. One of the areas in which it is most
quickly evolving is the sequencing and timing of therapies. This has been an
area of somewhat confusion, but we have also been able to make a significant
impact on outcomes. Patients can live longer and have more time being in
control of their cancer.
We
are using these therapies that were initially approved in the metastatic
castration-resistant setting early on. A lot of these are secondary
androgen-targeting agents, such as enzalutamide (Xtandi) and apalutamide
(Erleada). Abiraterone acetate and chemotherapy regimens, such as docetaxel—and
these drugs have been around for quite a while—are being utilized in this space
effectively. We're using them earlier. We're treating patients a lot more
aggressively than we were 5 years ago. The duration of control of the disease
is being extended.
We
are seeing this in large international studies such as CHAARTED or the STAMPEDE
trial. That is where the most change is occurring. There are some efforts
investigating things like immunotherapy in prostate cancer. That's been a
challenging area, but there are a lot of people working on it and it has some
potential in this field. We've seen a couple responders with immunotherapy; we
just need a better understanding of the biology. This is an area where we can
see some breakthrough in the next 5 years.
Are there any
indications as to a patient population who might best respond to immunotherapy?
We
don't know quite yet, especially in prostate cancer. How to select patients for
this type of treatment is tricky, and it's something we definitely need more
data for. We will hopefully see that in the next few years. It's an area of
ongoing investigation.
We
have some trials at our institution looking at combining a PARP inhibitor with
an anti–PD-1 agent. This is a novel approach. There are others looking at the
combination of ipilimumab (Yervoy) and nivolumab, which we've seen have promise
in other cancer types. We have some hope here, and we'll see how it plays out.
We've seen some responses, as I said before. It's just a matter of figuring out
the right combination.
What are the
remaining questions with regard to sequencing?
We
have a lot of drugs now, especially those targeting the testosterone and
androgen pathway. Several of them have shown success, and now there is a
question of which one is optimal. Could these be combined with another therapy?
Also, there is the chemotherapy question. Docetaxel given in the metastatic
castrate-sensitive setting has been shown to improve survival. However, so has
abiraterone. Some patients are receiving either one. This is going to be a big
question. Which therapies should we be using upfront? We have to test them head
to head.
The
other question is of radium-223 dichloride (Xofigo). It's an infusion that
targets bone metastases, and it's shown efficacy in castration-resistant
patients. We have to see where this really fits in.
References
1. Kyriakopoulos C, Chen Y, Carducci M, et al. Chemohormonal
therapy in metastatic hormone-sensitive prostate cancer: long-term survival
analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol.
2018;36(11):1080-1087. doi: 10.1200/JCO.2017.75.3657.
2. James N, de Bono
J, Spears M, et al. Abiraterone for prostate cancer not previously treated with
hormone therapy. N Engl J Med. 2017;377:338-351. doi: 10.1056/NEJMoa1702900.
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ANO7 Gene Linked to Aggressive Prostate Cancer | Cancer Network
John Schieszer Sep 20, 2018
The
prostate-specific (anoctamin 7) ANO7 gene may be a key player in the
development of aggressive prostate cancer, found a new European study published
in the International Journal of Cancer. By elevating the expression of ANO7, a
potential prostate cancer susceptibility gene, it may be possible to predict
disease severity and outcome, according to the researchers.
“We
have hypothesized for a long time that, at the molecular level, there's
probably a continuum of diseases that we now call prostate cancer. Prostate
cancer has a wide spectrum of clinical behavior that ranges from decades of
indolence to rapid metastatic progression and lethality. The biggest treatment
challenge is determination of aggressive cancers already in early phases of the
disease,” said study investigator Johanna Schleutker, PhD, professor of medical
genetics, Institute of Biomedicine, University of Turku/Division of Laboratory,
Turku University Hospital, Turku, Finland.
Schleutker
and her colleagues sequenced ANO7 in castration-resistant tumors together with
samples from unselected prostate cancer patients and unaffected men. The team
uncovered two pathogenic variants which were then genotyped in 1,769 men with
prostate cancer and 1,711 men without prostate cancer. Different databases
along with Swedish and Norwegian cohors were used to help validate the
findings.
Variant
rs77559646 was associated with increased risk (OR 1.40; 95% CI, 1.09-1.78; P =
.009) and with aggressive prostate cancer (Genotype test, P = .04). In
addition, rs148609049 was not associated with prostate cancer risk, but was
related to shorter survival (HR, 1.56; 95% CI, 1.03-2.36). Overall, high ANO7
expression was independently linked to poor survival (HR, 18.4; 95% CI,
1.43-237).
Currently,
there is no clear way to diagnose aggressive prostate cancer at an early stage.
However, genetic mutations such as those revealed in this study could lead to
the development of accurate diagnostic tests. “Obviously, more research is
needed to understand the mechanisms behind our findings. However, it is very
likely that genomics will become an important tool for decision-making in
prostate cancer treatment,” Schleutker told Cancer Network. Genetic testing for
ANO7 could provide new opportunities for precision oncology in prostate cancer,
she added.
The
researchers noted that although this study involved a large population, it is
limited by the fact that it primarily consists of Caucasians from Northern
Europe. Further research involving other demographics is warranted to validate
the findings, they noted.
William
Catalona, MD, a professor of urology at Northwestern Medicine Feinberg School
of Medicine, Chicago, said this study and others are providing an increased
understanding of the genomics of prostate cancer. For instance, germline
variants associated with deficiencies of DNA repair have been shown to increase
the susceptibility to prostate cancer and its aggressiveness.
“This
information has helped define distinct genomic pathways with different clinical
outcomes [that] respond to different treatments,” Catalona told Cancer Network.
“This excellent study performed by a highly-respected, experienced research
team has identified a relatively rare genetic variant that could be
inexpensively genotyped as part of a biomarker panel that, along with other
parameters, could help distinguish men with aggressive prostate cancer. The
authors’ caveat about validation in non-northern European white populations is
important,” he confirmed.
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Complications of Androgen Deprivation Therapy in Men With Prostate Cancer
Tejas Patil, MDBrandon Bernard, MD, MPH
Sep 18, 2018 Volume: 32 Issue: 9 Prostate Cancer, Genitourinary Cancers, Oncology Journal Oncology (Williston Park). 32(9):470-4, CV3.
Sep 18, 2018 Volume: 32 Issue: 9 Prostate Cancer, Genitourinary Cancers, Oncology Journal Oncology (Williston Park). 32(9):470-4, CV3.
Table. Major Side Effects Associated
With Androgen Deprivation Therapy (ADT)
Abstract /
Synopsis:
The
standard treatment for men with metastatic prostate cancer is androgen
deprivation therapy (ADT). This therapy is associated with a multitude of side
effects that can impact quality of life. These include vasomotor complications
(in particular, hot flushes), sexual dysfunction and gynecomastia,
osteoporosis, metabolic syndrome, and depression. Additionally, ADT has been
associated with neurocognitive deficits, thromboembolic disease, and
cardiovascular disease, although the data regarding the latter associations are
mixed. This article summarizes the key side effects associated with ADT and
discusses strategies to optimize management.
Introduction
Metastatic
prostate cancer remains a global health challenge. Despite improvements in
anticancer therapies, management of the disease is often a struggle to maintain
a balance between preserving quality of life and extending survival. Charles
Huggins and Andrew Schally laid the groundwork for establishing the critical
role of antiandrogen therapies in the management of metastatic prostate
cancer.[1] Initially, androgen deprivation therapy (ADT) was achieved via
orchiectomy, but by the mid-1980s, the approval of gonadotropin-releasing
hormone (GnRH) agonists allowed for medical ADT.[2] Intermittent ADT represents
an option for patients with biochemically relapsed prostate cancer, but
continuous ADT is the standard initial treatment for metastatic disease. While
prolonged disease control can be achieved with this approach, use of ADT is
associated with a wide range of side effects (Table) that may significantly
reduce quality of life. In this article, we summarize the key side effects
associated with ADT and highlight strategies to mitigate them.
Vasomotor
Complications
Hot
flushes are one of the most common and bothersome side effects associated with
ADT. Up to 80% of patients undergoing treatment with GnRH agonists will
experience hot flushes, with 27% of these patients reporting this symptom as
the most significant adverse side effect.[3] Hot flushes are described as an
intense feeling of warmth, occasionally associated with nausea and night
sweats. Many patients will achieve some improvement in symptom severity as
their bodies acclimate to the low testosterone state, although some patients
will not acclimate. Therapeutic management is largely extrapolated from studies
in breast cancer patients receiving tamoxifen.[4] Randomized clinical trials
have demonstrated efficacy of gabapentin and venlafaxine; these agents may be
used for this off-label indication in men receiving ADT.[5,6] Low-dose estrogen
and progestins can also be considered,[5] but the benefits of this option need
to be weighed against the thromboembolic risk associated with estrogen use.[7]
Additionally, acupuncture has been shown to be of potential benefit.[8]
Conservative strategies to abort hot flushes include sleeping with an open
window or drinking cold beverages. Lastly, regular exercise can help decrease
frequency and severity of hot flushes; given the benefit of exercise for other
ADT side effects and overall health, this recommendation is strongly
encouraged. Overall, a stepwise approach is suggested for hot flush management,
including exercise, conservative measures, use of venlafaxine or gabapentin,
and lastly use of estrogen or progestins as needed, while weighing the
potential risks vs benefits of each treatment option.
Sexual
Dysfunction and Gynecomastia
Several
studies have shown that treatment for clinically localized prostate cancer
involving either radical prostatectomy, brachytherapy, or external beam
radiotherapy (EBRT) can result in long-term erectile dysfunction.[9,10]
Patients receiving neoadjuvant ADT with EBRT were found to have decreased
frequency of erection, decreased overall sexual function, and an increase in
frequency of hot flushes.[11] In addition, loss of libido is a major
consequence of ADT. The degree of erectile dysfunction for patients on ADT is
impacted by pretreatment sexual function, as well as by changes in libido; in
patients previously able to attain an erection, phosphodiesterase 5 inhibitors,
intracavernosal injection therapy, vacuum-assisted devices, or other topical
agents may be used. Given the complex interplay between physiology, psychology,
stress, and emotion involved in sexual function, a referral to a psychology or
counseling service with a focus on sexual health is recommended for interested
patients and their partners.
Gynecomastia
may arise in conditions of unopposed estrogen activity and can be distressing
for cosmetic reasons or because of pain. It may occur with ADT; however, it is
more problematic with antiandrogens (specifically at higher doses) due to the
buildup of androgens and their consequent peripheral conversion to estrogen in
breast tissue. Tamoxifen and breast irradiation are two treatment options; the
former is more beneficial as primary prevention, whereas the latter may be of
greater use following established gynecomastia.[12,13]
Bone Health
ADT
is associated with significant changes in bone. Multiple studies have
demonstrated that bone mineral density (BMD) is significantly reduced in men
receiving ADT compared with controls.[14] The risk of fracture increases with
use of ADT and appears to be dose dependent.[15] Prevention of skeletal-related
events (SREs) has been evaluated in multiple randomized clinical trials for
patients with nonmetastatic castration-sensitive prostate cancer (CSPC). One
study demonstrated a significant decrease in BMD in men receiving ADT alone,
while there was no significant change in those who received ADT plus pamidronate.[16]
In castration-resistant prostate cancer (CRPC) metastatic to bone, a randomized
placebo-controlled trial found that zoledronic acid reduced SREs.[17] Another
phase III randomized clinical trial found denosumab to be more effective than
zoledronic acid in preventing SREs.[18] Interestingly, in contrast to men with
metastatic CRPC, no benefit was seen from osteoclast inhibition in men with
CSPC metastatic to bone.[19]
Men
who are about to start ADT should be evaluated for risk of osteoporosis, prior
fractures, alcohol use, and prior (or current) glucocorticoid use. Serum
vitamin D and baseline BMD may be checked to see if bisphosphonates are
indicated, with periodic re-evaluation of BMD while on ADT. For all patients
starting ADT, it is recommended that they supplement their diet with at least
1,000-mg oral calcium daily and 1,000 IU of vitamin D in an effort to preserve
bone integrity and minimize losses; a referral to a registered dietician may
further aid in refining both dietary and supplement recommendations. Lastly, an
exercise program that includes resistance training and/or weight-bearing
exercise is encouraged to further maintain bone strength.
Metabolic
Syndrome
A
variety of metabolic changes have been observed with ADT, including weight gain,
dyslipidemia, hyperglycemia, and sarcopenia. Weight gain, specifically, is a
well-recognized side effect of ADT.[20-22] Retrospective studies have found
that men on ADT for nonmetastatic prostate cancer had a median weight gain of 1
to 2 kg after 1 year of treatment.[22] Similar changes in weight have been
noted in the metastatic setting.[23-25] When more dramatic, weight gain can
have major consequences in terms of both mental and cardiovascular health. A
referral to a registered dietician may help with improving diet, while
engagement in a structured and formal exercise program can help with reducing
or maintaining weight. Many cancer centers offer such programs, and these
should be suggested to interested or at-risk patients.
In
addition, multiple studies have noted dyslipidemia and increased risk for
metabolic syndrome with use of ADT.[26,27] Extrapolating that these changes are
associated with increases in cardiovascular risk remains controversial. Loss of
lean muscle mass and sarcopenic obesity have been described in several studies.
A study of 39 men receiving ADT using CT measurements of the rectus, femoris,
sartorius, and quadriceps muscles noted decreases in the cross-sectional area
of these muscles.[28] Given the importance of these muscles in gait and
balance, studies have explored the association between ADT use and fall risk.
One study noted a higher rate of falls in persons treated with ADT, with
apparent persistent risk even after ADT is discontinued.[29] Thus, judicious
use of ADT and careful evaluation of frail patients and those at risk for
complications are recommended when the need for treatment is questionable (eg,
biochemical relapse with slowly rising prostate-specific antigen [PSA] levels).
Neurocognitive
Changes
Emerging
data show that men with prostate cancer receiving ADT are at risk for a
spectrum of neurocognitive complications, such as depression, memory
difficulties, and fatigue.[30] In a population-based cross-sectional study of
elderly men, it was found that lower serum testosterone levels were associated
with decreased performance on the Mini-Mental State Examination (MMSE), the
Trail Making Test B, and the Digit Symbol Substitution cognitive test. A major
confounding variable in this study was age, since more than half of all cases
of dementia occur in men > 65 years of age. This was addressed in a large
cohort study that found a statistically significant association between use of
ADT and risk of dementia.[31] Sensitivity analyses found that use of ADT for
longer than 12 months was associated with the greatest absolute risk of
dementia.
Numerous
prospective studies examining the impact of ADT on cognitive function have been
performed, with mixed and conflicting results. A prospective study of men with
extraprostatic disease randomized 82 patients to receive either leuprolide,
goserelin, cyproterone acetate, or close clinical monitoring. All patients
underwent serial cognitive assessments at baseline, at the start of treatment,
and at 6 months.[32] A decrease in cognitive performance after 6 months of ADT
use was found in the patients on active treatment compared with those on the
close monitoring arm. A major limitation of this study is that spatial memory
testing was omitted from the analysis, which has been shown to be more
sensitive in detecting cognitive differences.[33] Another cross-sectional study
compared neuropsychological parameters in three groups of patients: patients
with prostate cancer receiving ADT, patients with prostate cancer not receiving
ADT, and normal controls.[34] Here, the authors made a distinction between
time-based prospective memory (eg, remembering to call a friend in 1 hour) and
event-based prospective memory (eg, remembering to buy fruit when passing a
fruit stand). This study demonstrated that men receiving ADT did demonstrably
worse in event-related prospective memory than men not receiving ADT and
matched controls. A limitation of this study was the lack of long-term
follow-up on cognitive function, making it difficult to know whether the neurocognitive
effects of ADT persist after discontinuation of therapy.
These
studies can be contrasted with several others that have not demonstrated an
association between use of ADT and neurocognitive decline. A large cohort study
compared cognitive function using neuropsychological tests in the following
groups: men with prostate cancer receiving continuous ADT, men with prostate
cancer not receiving ADT, and healthy controls.[35] The authors found no
difference in cognitive function over 12 months of ADT use. Furthermore, a
recent large meta-analysis failed to find an association between cognitive
impairment and ADT.[36] Similar findings were reported in one of the largest
population studies of this kind, which examined 1.2 million Medicare
beneficiaries who developed prostate cancer from 2001 to 2014.[37] The risk of
dementia was not associated with duration of ADT (ie, there was no
dose-dependent effect). Currently, there is mixed evidence on whether ADT is
associated with long-term neurocognitive impairments, and this remains a topic
of active research. In patients with baseline cognitive impairment, it is
reasonable to attempt to minimize exposure to ADT, if possible (through
intermittent treatment or by treating with anti-androgen monotherapy).
Thrombotic
Complications
Thromboembolic
risk has been noted in several studies.[31,38] In a large retrospective series,
patients who received ADT had a 15% absolute risk of venous thromboembolism
(VTE), compared with 7% among patients who did not receive ADT. Overall, there
was a significant association between ADT use and risk of VTE or arterial
embolism (adjusted hazard ratio [HR], 1.56; 95% CI, 1.50–1.61; P < .0001).
Furthermore, greater duration of ADT was associated with an increased number of
VTE events. These data are especially important to consider in patients with
additional risk factors for VTE. Indeed, as indicated previously, tamoxifen has
been reported to be useful therapy for ADT-associated gynecomastia,[13] yet it
is an independent risk factor for thrombosis. Breast irradiation can be an
alternative in symptomatic patients with thrombotic risk.
Data
regarding use of ADT and risk of stroke are conflicting. A prospective
case-control study from Taiwan reported no increased risk of stroke in patients
with prostate cancer receiving ADT vs those not receiving it in an adjusted
analysis.[39] In contrast, a meta-analysis reported a trend toward increased
risk of stroke with ADT; however, this was not statistically significant (HR,
1.12; 95% CI, 0.95–1.32; P = .16). That said, subgroup analysis did identify
GnRH agonist use alone or combined with anti-androgen use, and surgical
castration, as having a significant association with stroke.[40] Based on the
available evidence, risk of stroke should be mentioned when obtaining informed
consent; however, the individual absolute risk is likely low.
Cardiovascular
Complications
There
are conflicting data on the risk of cardiovascular disease (CVD) with use of
ADT. Currently, there are no prospective randomized controlled data assessing
the association of ADT use with risk of CVD. In a large retrospective
population-based cohort study, multivariate analyses demonstrated that men with
newly diagnosed prostate cancer who received ADT had a 20% increased risk of
CVD.[41] Somewhat paradoxically, the study found that men receiving treatment
for less than 12 months were at higher risk for cardiovascular events compared
with men who had been on ADT for longer. A major limitation of this study is
that the researchers were unable to control for smoking and obesity, which are
two major risk factors for CVD and could confound the results. Additionally,
age was a major variable associated with CVD. A meta-analysis of eight large
trials found no significant differences in risk of CVD in patients receiving
ADT vs controls, nor was duration of ADT significantly associated with
increased risk of CVD.[42]
KEY POINTS
·
Vasomotor
complications are common in men receiving androgen deprivation therapy (ADT)
and can be mitigated by pharmacologic and nonpharmacologic strategies.
·
There
is an increased risk of osteoporosis and skeletal-related events in men
receiving ADT. Calcium and vitamin D supplements should be offered to all
patients. Osteoclast inhibitors should be considered in men at high risk for
osteoporotic fractures and men with metastatic castration-resistant prostate
cancer.
·
Evidence
on the association between ADT use and neurocognitive decline and
cardiovascular disease remains mixed and controversial.
·
Multidisciplinary
management with specialists and allied health professionals may assist in
managing the complex side effects of ADT.
Currently,
no specific recommendation adjustments for men with prostate cancer receiving
ADT should be pursued outside of primary prevention, including smoking
cessation, and secondary prevention, including glycemic control, lipid-lowering
therapy, and aspirin therapy for men with coronary artery disease. Given the
propensity of patients on ADT to gain central adiposity, a healthy diet and
exercise program are recommended to all patients at the start of treatment.
Intermittent ADT or antiandrogen monotherapy may be appropriate for select
patients (eg, those with biochemical relapse, low burden of metastases with
more indolent course, and deep PSA nadir) at high risk for cardiovascular
events; such patients should be evaluated on an individual basis and engaged in
shared decision making, weighing the risk of a cardiovascular event vs cancer
progression. Ultimately, patients with known CVD or those with numerous CVD
risk factors should be evaluated promptly, if they develop new symptoms of
chest pain or dyspnea while on ADT. A referral to cardio-oncology may assist in
risk stratification.
Renal
Complications
Observational
data suggest an association between ADT use and rate of acute kidney injury
(AKI).[43,44] In retrospective studies, the link appeared stronger with use of
GnRH agonists plus an antiandrogen, as well as with GnRH agonists alone,
compared with surgical castration; however, the inherent biases within such
studies and the potential for numerous confounders raise questions regarding
causality and the strength of association. Thus, use of ADT may present an
increased risk of AKI, although the true risk and clinical significance are
difficult to quantify.
Conclusion
ADT
is the cornerstone of management for men with metastatic prostate cancer. It is
associated with numerous side effects that can influence quality of life. Hot
flushes, sexual dysfunction, gynecomastia, osteoporosis, metabolic syndrome,
and depression are well-described complications of ADT. The implications of ADT
use for risks of neurocognitive decline and CVD remain controversial, with
multiple studies documenting conflicting results. Addressing quality-of-life
concerns is of paramount importance with use of ADT, given the increased
survival benefits found with combinations of ADT with other agents. Given the
advanced age of many patients and the prolonged duration of ADT when treating
localized disease with curative intent, some patients remain hypogonadal long
after completion of therapy, underscoring the potential long-lasting sequelae
of treatment. While consensus is lacking, there are mounting data[45]
suggesting that testosterone replacement therapy may be cautiously used in
select individuals in whom risk of prostate cancer relapse is determined to be
low and hypogonadism remains long after ADT cessation. Ultimately, applying a
multidisciplinary care model that incorporates specialists and allied
healthcare professionals to aid in pharmacologic and lifestyle interventions is
likely to provide optimal benefit in managing side effects for patients
receiving long-term ADT.
Financial
Disclosure: The authors have no significant financial interest in or other
relationship with the manufacturer of any product or provider of any service
mentioned in this article.
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Curr Urol Rep. 2017;18:49
--------------------------------------------------------------------------------------------------------------------------------------
Aggressive prostate and lung cancers are driven by common mechanisms, researchers find
Date: October
4, 2018 Source: University of California - Los Angeles
Health Sciences
Summary:
Researchers
have discovered a common process in the development of late-stage, small cell
cancers of the prostate and lung. These shared molecular mechanisms could lead
to the development of drugs to treat not just prostate and lung cancers, but
small cell cancers of almost any organ.
A microscopic image of small cell neuroendocrine
prostate cancer, with cancer cells expressing diagnostic prostate cancer
markers in green and red. Blue areas indicate cell nuclei.
Credit: Jung Wook Park and Owen Witte
UCLA researchers have discovered a common process in
the development of late-stage, small cell cancers of the prostate and lung.
These shared molecular mechanisms could lead to the development of drugs to
treat not just prostate and lung cancers, but small cell cancers of almost any
organ.
The key finding: Prostate and lung cells have very
different patterns of gene expression when they're healthy, but almost
identical patterns when they transform into small cell cancers. The research
suggests that different types of small cell tumors evolve similarly, even when
they come from different organs.
The study, led by Dr. Owen Witte, founding director of
the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell
Research and professor of microbiology, immunology and molecular genetics, was
published in the journal Science. Witte collaborated with scientists from
UCLA's Crump Institute for Molecular Imaging and the UCLA Jonsson Comprehensive
Cancer Center.
Cancers that become resistant to treatment often
develop into small cell cancers -- also known as small cell neuroendocrine
carcinomas, or SCNCs -- which generally have extremely poor prognoses. Certain
cancers can evade treatment in part by changing cell types -- from aggressive
adenocarcinoma to small cell carcinoma, for example.
Previous research hinted that small cell cancers from
different organs may be driven by common mechanisms, but the UCLA study is the
first to so clearly describe the steps in their evolution.
"Small cell cancers of the lung, prostate,
bladder, and other tissues were long thought to be similar in name alone -- and
they were treated by oncologists as different entities," Witte said.
"Over the past few years, though, researchers have increasingly begun to
realize that there are similarities in the cancers, and that's what our work
confirms."
Dr. Jung Wook Park, the study's first author, and UCLA
collaborators explored the potential parallels between the cancer types by
transplanting human prostate cells with five genes, known collectively as
PARCB, into mice. When those cells grew in the mice, they displayed unique
features of human small cell neuroendocrine carcinomas.
The team also identified that for small cell
neuroendocrine carcinomas to develop in the prostate, two tumor suppressor
genes, TP53 and RB1, which are known for protecting normal cells from
transforming into cancer cells, had to be simultaneously inactivated when PARCB
was introduced.
Additional tests confirmed striking similarities
between the PARCB-SCNC cells and small cell prostate cancer cells from humans.
In particular, RNA expression and the turning on and off of certain genes were
nearly identical.
"The similarities between the PARCB-SCNC cancers
and human small cell prostate cancer samples were extraordinary," Witte
said. "If you blindly gave the data sets to any statistician, they would
think they were the same cells."
The team also looked at large databases of gene
expression, to compare the patterns of gene expression in their PARCB-SCNC
cells to cancers of other organs. They found that the pattern of gene
expression in PARCB-SCNC cells was extremely similar to those of both prostate
and lung small cell cancers.
Next, they tested whether PARCB genes could alter
healthy cells from human lungs into small cell lung cancers, and the scientists
found that they could.
The team now is working on mapping which genes control
the entire cascade of events that underlies the transition to small cell
cancer.
"Our study revealed shared 'master gene
regulators' -- the key proteins that control expression of multiple genes in
small cell cancer cells," Witte said. "Studying the network of the
master gene regulators could lead to a new way of combating deadly
cancers."
The research was supported by the Broad Stem Cell Research
Center Stem Cell Training Program and Hal Gaba Fund for Prostate Cancer
Research, the UCLA Medical Scientist Training Program, the UCLA Specialized
Program of Research Excellence in Prostate Cancer, the National Institutes of
Health, the National Cancer Institute, the Prostate Cancer Foundation, the
Department of Defense, the American Cancer Society and the W.M. Keck
Foundation.
Story Source:
Materials provided by University of California - Los
Angeles Health Sciences. Original written by Alice Walton. Note: Content may be
edited for style and length.
Journal Reference:
Jung Wook
Park, John K. Lee, Katherine M. Sheu, Liang Wang, Nikolas G. Balanis, Kim
Nguyen, Bryan A. Smith, Chen Cheng, Brandon L. Tsai, Donghui Cheng, Jiaoti
Huang, Siavash K. Kurdistani, Thomas G. Graeber, Owen N. Witte. Reprogramming
normal human epithelial tissues to a common, lethal neuroendocrine cancer
lineage. Science, 2018; 362 (6410): 91 DOI: 10.1126/science.aat5749
Additional Links:
Prostatepedia Weekly 10.4.18
Aggressive prostate and lung cancers are driven by common mechanisms, researchers find -- ScienceDaily: Researchers have discovered a common process in the development of late-stage, small cell cancers of the prostate and lung. These shared molecular mechanisms could lead to the development of drugs to treat not just prostate and lung cancers, but small cell cancers of almost any organ.
Can aspirin help treat cancer?: A systematic review of 71 studies suggests that regular aspirin intake may help treat cancers such as colon cancer, breast cancer, and prostate cancer.
Prostate cancer outcomes today vs. outcomes yesteryear | THE "NEW" PROSTATE CANCER INFOLINK: As some of us have long suspected and understood, using data from men treated 20+ years ago as a guide to what would happen if you were treated the same way today is not really a very good idea. A …
Multimodal Therapy May Up Survival in Advanced Prostate Cancer: But the notable survival advantage seen with primary treatment consisting of radical prostatectomy plus radiotherapy also came with a high cost to quality of life.
Free randomized clinical trial of gallium-68-PSMA-11 PET indicator | THE "NEW" PROSTATE CANCER INFOLINK: A randomized clinical trial of the 68Ga-PSMA-11 PET indicator for men with a recurrence after radical prostatectomy has just been initiated at the University of California Los Angeles (UCLA). Eligi…
68Ga-PSMA-11 PET/CT in Newly Diagnosed Prostate Adenocarcino... : Clinical Nuclear Medicine: newly diagnosed PCa.
Materials and Methods
A total of 78 patients with biopsy-proven PCa who were referred for 68Ga-PSMA-11 PET/CT for primary staging were retrospectively analyzed. The patients were divided into risk groups according to the D'Amico risk stratification criteria. All of the patients had undergone pelvic MRI, and 65 patients had bone scintigraphy also. The findings of 68Ga-PSMA-11 PET/CT were compared with these conventional imaging (CI) methods for staging of the disease. The relations between SUVmax of the primary tumors and Gleason scores (GSs), prostate-specific antigen (PSA) levels, and metastatic extent of the disease were analyzed.
Results
Of 78 patients, 5 patients were in low-risk group, 18 patients were in intermediate-risk group, and 55 patients were in high-risk group. Metastatic disease was found in 40 (51.2%) of 78 patients in 68Ga-PSMA-11 PET/CT. Ten patients had regional lymph node metastases, and 30 patients had distant metastases. 68Ga-PSMA-11 PET/CT changed the staging in 44 (56.4%) of 78 patients compared with CI. There was significant difference between the SUVmax of the tumors with GSs of 6 and 7 compared with GSs of 8, 9, and 10 (P = 0.003).
Radical Prostatectomy Plus Radiotherapy Extends OS in Prostate Cancer | Cancer Network: A study in Cancer found a lower risk of prostate cancer–specific death and improved overall survival when patients were treated with this combination.
[Concordance evaluation of gleason score between laparoscopic prostatectomy and needle biopsy specimens]. - PubMed - NCBI: Wiad Lek. 2018;71(6):1193-1199. English Abstract
Salvage extended field or involved field nodal irradiation in 18F-fluorocholine PET/CT oligorecurrent nodal failures from prostate cancer | SpringerLink: Purpose The concept of metastasis-directed therapy for nodal oligorecurrences with stereotactic body radiotherapy is increasingly accepted. Hence, the comparison between salvage extended field...
