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MY EXPERIENCE WITH PROSTATE CANCER PATIENTS WHO PRESENTED
WITH SIDE EFFECTS OF ANDROGEN DEPRIVATION THEREPY (ADT) SINCE 2007
AND REVIEW OF LITERATURE:
ABSTRACT:
The major male androgen called Testosterone is required for the determination of
male phenotype. It is also necessary for the growth, homeostasis and function of
the prostate gland; hence the prostate gland is an androgen – dependent organ.
Prostrate cancer is also androgen dependent and androgen suppression is the
mainstay of treatment for locally advanced and metastatic disease. Historically,
bilateral orchidectomy was the only effective androgen deprivation therapy (ADT).
Later on, luteinizing hormone – releasing hormone (LHRH) agonists were
introduced to reduce testosterone to castrate levels. These treatment modalities are
however palliative leading to a median progression– free survival of 18-20 months
and an overall survival of 24-36 months. ADT may be associated with significant
and sometimes durable responses, but its potential efficacy is further limited by an
array of significant and bothersome side effects that ultimately affect patients
quality of life (Qol).
The aim of this article is to put together my experiences with patients who
presented with side effects of ADT, review of relevant literature and to comment
that all intended patients should be properly counselled to avoid regrets and
abandonment of care due to troublesome side effects.
Key words: Experience, androgen deprivation therapy, side effects.
INTRODUCTION:
The testes are the major sources of testosterone in men. It is secreted by the
Leidig cells of the testes under the influence of luteinizing hormone secreted by
the cells of the anterior pituitary gland. The pituitary gland secretion is further
controlled by the luteinizing hormone–releasing hormone (LHRH) produced in
the hypothalamus. The remaining androgens originate from the supra-renal
gland hormones
that are enzymatically converted to testosterone and
dihydrotestosterone in prostate and peripheral tissues. The growth of normal
cells of the prostate gland and also prostate cancer cells are dependent on these
hormones. Thus androgen deprivation is one of the main treatment modalities in
the management of prostate cancer.
Historically, bilateral orchidectomy, which achieves 95% reduction in
testosterone levels within 3hours, was the only effective ADT1. Estrogens have
also been used for treating metastatic prostate cancer, however, it use has been
associated with significant cardiovascular morbidity and even mortality. In the
1980’s, LHRH agonists were introduced to reduce testosterone to castrate
levels. After the 1980’s, non-steroidal anti-androgen were developed in addition
to steroidal anti-androgen2. Another modality such as maximum androgen
blockade, which is a combination of surgical or medical castration and an oral
anti androgen, has also been in use. More recently, intermittent androgen
suppression has been developed and used.
ADT mainly addresses treatment by bilateral orchidectomy or with LHRH
agonists plus an anti-androgen. Monotherapy with an anti-androgen is an
alternative form of hormone therapy that is associated with fewer side effects
and they do not represent a form of medical castration since they elevate rather
than lower serum testosterone levels3 . ADT whether medical or surgical
provides important quality of life benefits in patients with locally advanced and
metastatic prostate cancer. The benefits include but not limited to decreased
rates of spinal cord compression, ureteric obstruction, extra-skeletal metastasis
and pathological fractures4. On the other hand, it is not clear whether there is an
improvement in overall survival in patients with metastatic disease5. However,
ADT use is associated with multiple and significant side effects related to
decrease of testosterone. Given this, it is considerate to assign patients to ADT
only when necessary since not every prostate cancer patient will die due to the
disease. The side effects of ADT, from decreased serum testosterone level
which may be short term and long term include hot flashes, loss of libido, loss
of muscle mass, fatigue, gynaecomastia, cognitive dysfunction, depression,
increased risk of fracture, increased incidence of osteoporosis, diabetes and
cardiovascular morbidity and mortality-6.
A syndrome called andropause has been well studied and documented. It is
defined as an age-related decline in serum testosterone levels in older men to
below normal range in young men which is associated with a clinical syndrome
consistent with androgen deficiency. The syndrome may include decreased
pubic and auxiliary hair, reduced physical function, diminished libido, fatigue,
depressed
mood,
decreased
generalized
well
being,
hot
flashes,
osteopenia/osteoporosis and anaemia6. Thus, the side effects of ADT
superimposed in aged men with underlying symptoms and signs of andropause
can be deleterious. Hence the importance of understanding and recognizing
these side effects as well as a thorough discussion about the pros and cons of
treatment with the patient are needed.
METHOLOGY:
This paper is born out of my numerous experiences with patients who presented
with side effects of ADT over the years ( since 2007 ). Information were
collected from personal interview with them during their routine clinic visits, in
accident and emergency room as a result of complications and in male surgical
wards when admitted on account of serious side-effects. Patients in this study
were on ADT for at least 3 months. ADT used included LHRH (e.g Goserelin
and Leuprolide) and bilateral orchidectomy and
Bicalutamide or Flutamide)
an antiandrogen
(e.g.
added to each of these
treatment modalities . It was a conscious effort to sit with them and document
their clinical symptoms, signs on physical examination and necessary imaging
techniques to come out with this paper. I will present my experience and review
relevant literature on this subject.
RESULTS:
Patients were seen with numerous side effects ranging from mild to severe
disabilities. The side effects included sexual dysfunction (including loss of
libido
and erectal dysfunction), changes in body composition
(e.g
gynaecomastia and reduced muscle mass and tone) cognitive defect, sleep
disturbance, hot flashes, anaemia with fatigue that required frequent blood
transfusions. The less common ones were relationship changes, fracture,
diabetes, osteoporosis. Flare phenomenon was not
encountered because of
concomittant use of antiandrogen with LHRH agonist.
DISCUSSION:
The principle of ADT is to achieve serum testosterone concentration as low as
possible to minimize stimulation of prostate cancer cells. Serum testosterone
concentrations that correspond to castrate levels have generally been set at less
than 50ng/dl (<1.7nmol/l)7. However, most men achieve levels below 20ng/dl
(0.7nmol/l) after orchidectomy and it has been suggested that castration levels
should be redefined to reflect this threshold8. Unfortunately, decreased
testosterone levels are well known with their short-term and long-term adverse
effects. The frequently encountered side effects in this study included:
SEXUAL DYSFUNCTION:
Sexual dysfunction prominently noticed are erectal dysfunction and loss of
libido. Normal testosterone level is necessary for these processes to remain
normal. Erectal dysfunction (ED) is a complex neurovascular phenomenon
modulated by several biochemical and physiological factors 9. The biochemical
marker identified here is testosterone which is the target in ADT. Low
testosterone levels have a direct effect on penile function by causing venous
leak in prostate cancer patients and phosphodiesterase -5 inhibitor works poorly
in low testosterone environment10. However, it has been of note that a
significant decrease in testosterone level is observed in the aging process11.
Also among aging males, there is a high prevalence of diabetes mellitus and
hypertension which can also contribute to ED in their different ways. Gurbuz et
al11 also found out that many older men have sexual dysfunction at baseline
prior to ADT initiation and this should be identified before treatment is
commenced. ED can be quite devastating to both patients and partners. Casey
et al12 noted that ED can significantly affect the self-esteem, self perception and
quality of life of younger, sexually active men especially when coupled with the
side effects of ADT on muscle and fat distribution.
Loss of libido was also encountered top on the list in this study. It had been
quite distressing to these patients exacerbated by ADT use. Not all men on ADT
have loss of libido, suggesting that other factors may impact severity such as
testosterone level and or age. Ideally, the potential impact on all aspects of
sexual function needs to be assessed through forth-right discussion between
patients, their partners and their health care provider before starting ADT. The
ADT survivor group has recognized that patient’s lack of preparation for such
sexual changes results in regrets, anger or depression13.
ANAEMIA:
Anaemia was another common or frequent side effect noticed in these patient’s
population who received repeated blood transfusions and frequent hospital
admissions. Association between androgen and erythropoiesis had been known
for several decades. Androgens stimulate haemopoietic system via mechanisms
that include stimulation of erythropoietin release, increasing bone marrow
activity and iron incorporation into red cells14. Men with advanced or metastatic
prostate cancer are prone to developing anaemia due to several causes. It could
be due to blood loss as the cancer cells infiltrate the prostatic urethra and
bladder mucosa with subsequent sloughing or replacement of the bone marrow
with metastatic cells and thereby halting erythropoiesis. Moreover, testosterone
increases the production of erythrogenesis–stimulating proteins, so that ADT
may cause or exacerbate anaemia by indirectly inhibiting erythropoiesis 12.
Anaemia can also result from anorexia common in these patients.
HOT FLASHES (FLUSHES):
This was one of the most common and early side-effects. Patients described a
perception of intense heat in the head, neck region and abdomen lasting briefly
with subsequent cooling and sweating. They were usually anxious. Some
reported multiple episodes in a day while others perceived it occasionally. It is
actually a vasomotor phenomenon caused by inappropriate stimulation of
thermoregulatory centres in the hypothalamus resulting in peripheral
vasodilatation15. Aetiologically, hot flashes in men under ADT develop due to
acute withdrawal of sex hormone similar to what happens in women at the onset
of menopause. ADT disrupts the equilibrium of the neurotransmitters (NT)
increasing the levels of NT, norepinephrine and Serotonin and hormones
including testosterone. This effect in turn is postulated to deregulate the
haemostatic mechanism of the thermoregulatory centres in the preoptic zone of
the hypothalamus16. However, hot flashes may also be experienced on aging
males who are not on ADT, relating well known decrease in testosterone level
with aging. Results of a survey by Spetz A. et al17 showed that a third of
uncastrated men aged 55-75 years experienced hot flashes of whom 15% had
bothersome hot flashes.
GYNAECOMASTIA:
This was reported by many patiets and
very embarrassing. Usually very
painful. Some patients actually requested for surgery or out right change of
medications. This actually led to poor drugs compliance by these patients. It is
caused by an increase in the ratio of estrogen to androgen when on ADT.
Gynaecomastia usually starts within the first year of hormonal treatment and is
initially reversible. After it is present for about a year, however, hyalinization
and fibrosis occur, which are irreversible18.
MOOD AND COGNITIVE CHANGES:
This was also frequently reported by these patients on ADT.
The mere
diagnosis of cancer in a patient is enough to demoralize and also blunt his
mood. Depression is a normal aspect of adjustment to a diagnosis of cancer.
Hormonal therapy has also been shown to cause neurologic impairment,
manifested by decreased cognitive function, mood and self esteem while also
negatively affecting memory and attention19. Low levels of testosterone are
significantly associated with depression in elderly men and testosterone
replacement appears to reduce depressive symptoms in such patients20.
Cognitive side-effects are apparent almost immediately as shown in a recent 3month neoadjuvant trial and appear to be reversible after completing treatment;
however, sometimes the effects are only partially reversible at one year21. The
linkage between depression and low levels of serum testosterone remain unclear
and indeed may be related to patient’s age and co-morbidities as it is more
common in men over age 65 years22. Only one report by Rosenblatt and Mellow
addressed the issue between depression and ADT in prostate cancer patients.
They reported 3 patients who developed severe depression after starting either a
Gonadotrophin-releasing hormone (GnRH) agonist or a GnRH agonist and an
anti-androgen. In this report, depression was refractory to medical treatment and
improved only after discontinuation of the androgen blockade. Nevertheless,
those patients had multiple other possible aetiologies of depression, including
new cancer diagnosis, histories of alcohol abuse and many other
comorbidities23. Although, there appear to be specific mechanisms for
testosterone to directly impact cognition, it is possible that the side effects of
androgen ablation therapy (e.g. hot flashes, fatigue and anaemia) may contribute
indirectly to impaired cognition24.
FATIGUE AND SLEEP DISTURBANCES:
Fatigue as a feeling of extreme physical and mental tiredness was one of the
frequently reported side effect of ADT use. This can be caused by anaemia
which is common in prostate cancer patients. ADT also contribute to anaemia
by promoting testosterone deficiency. Comorbidities e.g. diabetes mellitus and
hypertension can also contribute to fatigue. Hot flashes have been specifically
linked to insomnia and disrupted sleep patterns and have been shown to
contribute to depression in elderly patients on ADT25.
RELATIONSHIP CHANGES:
In a few of the patients their relationships were strained due in most cases to
sexual dysfunction. Few of the men interviewed were widowers and aged and
so their relationship issues were not bothersome as against the relatively
younger ones who expressed great concern about their marriage. Reduced libido
can result in withdrawal of emotional and physical intimacy26 and can also lead
to significant partner distress27. In general, partners of prostate cancer sufferers
describe even more distress than their partners28.
MUSCULOSKELETAL MORBIDITY:
This was marked by bone pain which was frequently seen in those with
metastatic disease with or without treatment. Bone fractures were few because
of incorporation of Bisphosphonate in the treatment regimen. Skeletal X-Rays
obviously showed evidence of osteoporosis (reduced bone density). It is known
that bone turn-over and development are androgen dependent. Androgen
deprivation causes 3-5% annual bone decrease in bone mineral density (BMD)
and prostate cancer patients on ADT have a 6-17% lower BMD than eugonodal
men with prostate cancer29.
Mittan et al in their work demonstrated a significant loss of bone in men with
prostate cancer receiving GnRH30. Androgen ablation is a cause of skeletalrelated events associated with significant morbidity and mortality even for
patients with non-metastatic prostate cancer. Risk factors for osteoporotic
fractures include the duration of ADT (>3years), age (mainly through decreased
testosterone level) ethnicity (Caucasians patients are at greater risk) smoking,
lower body mass index (BMI) and medications (e.g Glucocorticoids)31.
METABOLIC SYNDROME:
Most of the patients seen with diabetes were diagnosed before ADT was
commenced and all patients were screened with a fasting blood sugar (FBS)
estimation on presentation bearing in mind that urinary frequency is common in
both conditions. Another study is ongoing to unravel the relationship between
ADT use and development of diabetes. However, Gustavo FC32 in his review
noted that ADT is associated with several metabolic disorders such as increased
incidence of hyperglycaemia, insulin resistance, metabolic syndrome and
dyslipidaemia. According to the Adult treatment panel III criteria, metabolic
syndrome is present if three of the following five criteria are met: fasting
plasma glucose level more than 110mg/dl, serum triglyceride level > 150mg/dl,
serum high density lipoprotein (HDL) level less than 40mg/dl, waist
circumference more than 102cm and blood pressure of > 130/85mmHg33.
COST OF ANDROGEN DEPRIVATION DRUGS:
Although this is not directly a side effect of these medications, poor compliance
also stemed from financial constraints. Having in mind the population of men
in focus; most of them are retirees whose pensions may not be forth coming and
meager. They got financially distressed on commencement and could not
continue with this treatment which was the best option for them in tandem with
their disease state.
CONCLUSION:
ADT has come to stay as the treatment of choice for locally advanced and
metastatic prostate cancer. Aside from the benefits derived from ADT use with
associated significant and sometimes durable responses, it is not considered a
curative measure. Most importantly, numerous bothersome side effects have
been known that may adversely affect the quality of life of both the patient and
his partner. Therefore, before starting ADT, the patient and his partner should
be properly counselled. Other co-morbidities should be sort for and addressed in
the course of evaluation, knowing that these diseases can be more fatal that
prostate cancer let alone the morbid side effects of ADT.