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T3–4 disease and median PSA was 19ng/ml. Results presented at a national Due to these adverse physiological changes, a number of recent studies have
meeting after a median follow-up of five years showed that patients who been performed to evaluate the incidence of cardiovascular disease in
remained on ADT for three years had significantly better OS, CSS, and androgen-suppressed patients and its influence on survival. A population-
biochemical control. Thus, the existing data suggest that in the group of based study of over 70,000 men with non-metastatic prostate cancer found
high-risk, locally advanced patients seen more commonly in an earlier era, that rates of incident diabetes, incident coronary artery disease, myocardial
long-term ADT of two to three years with EBRT to 65–70Gy leads to infarction (MI), and sudden cardiac death were all incrementally higher in
improved OS. men treated with GnRH agonists.
D’Amico et al. performed a pooled
analysis of the three above-mentioned trials to evaluate the incidence of fatal
In the aforementioned retrospective analyses of patients treated with MI, and found that in men 65 years of age or older three to eight months of
brachytherapy and supplemental EBRT,
there was no difference seen ADT was associated with increased fatal MIs compared with men treated
between more than six months compared with less than six months of with radiotherapy alone.
There was an insufficient number of events in
ADT. This may be a reflection of response in patients with a more patients under 65 years of age to draw any conclusions in this age group.
favorable risk profile, i.e. longer-term ADT does not confer additional Similar results were reported from an analysis of a prostate cancer registry:
benefit in this group. Based on these data, a shorter course may be patients 65 years of age or older treated with definitive radiation had a
adequate with brachytherapy. higher five-year estimate of cardiovascular death of 8.4% with ADT versus
5.7% without, although this was not statistically significant (p=0.20).
The optimal timing of androgen suppression is not entirely clear as the However, there was a statistically increased risk for cardiovascular death in
main EBRT trials used adjuvant, neoadjuvant and concurrent, and patients of all ages treated with radical prostatectomy and ADT. Careful
concurrent and adjuvant, as well as neoadjuvant, concurrent, and adjuvant examination of the data reveals that many of the cardiovascular events occur
regimens. The interaction of androgen suppression with radiation is years after discontinuation of ADT, which is either a reflection of unbalanced
complex, as evidenced by recent results of RTOG 94-1335, which showed baseline cardiovascular risk factors or the latency and irreversibility of the
improvement in survival with neoadjuvant and concurrent ADT with pelvic early effects of ADT. Testosterone recovery can take eight to 18 months,
radiation, but a survival detriment with short-term adjuvant ADT. Given the during which time patients are still at risk for toxicities.
observed in vitro synergistic effects, most would advocate for concurrent
ADT with EBRT if it is to be given. Given the recent heightened awareness of the influence of the cardiovascular
system, these particular data have been reviewed for landmark randomized
Adverse Effects and Their Impact on Survival trials. In an update of RTOG 86-10, there was no statistically significant
ADT influences quality of life significantly enough for some men to difference in 10-year rates of cardiovascular deaths: 12.5% versus 9%
discontinue therapy before the recommended length of treatment. There without ADT (p=0.32).
An updated analysis of RTOG 92-02 was performed:
are numerous adverse effects resulting from induced hypogonadism: the five-year rate of cardiovascular mortality was approximately 5% with both
sexual dysfunction, hot flashes, weight gain, mood lability, sleep long- and short-term ADT and 10% in the subset of patients with a history of
disturbance, gynecomastia, shrinkage of genitalia, decrease in bone cardiovascular disease.
Data from EORTC 22961 showed no difference in
density, depression, and cognitive decline. More recently, there has been cardiovascular disease between six months and three years of ADT.
heightened concern regarding adverse physiological alterations that can were post hoc analyses and, as such, have their limitations. In future trials, it
influence OS. Androgen suppression alters body composition by both would be worth noting the proportion of patients in each arm treated with
decreasing lean body mass and increasing fat mass, even in the setting of ADT at the time of recurrence, as this would also contribute to the incidence
short-term androgen suppression.
Also, it has become evident that of associated morbidity through the follow-up period.
there is a direct relationship between a low testosterone level and
decreased insulin sensitivity, which is supported by improvement with Increased risk for fracture secondary to ADT may also contribute to the
testosterone replacement in hypogonadal men.
ADT initially induces survival equation when balancing the risks and benefits of treatment.
hyperinsulinemia, which maintains euglycemia; however, with longer Androgen suppression has been shown in numerous studies to decrease
androgen suppression, hyperglycemia and frank diabetes develop.
In one bone mineral density.
ADT for prostate cancer is now one of the leading
study, 44% of men who received ADT for at least 12 months developed causes of osteoporosis in the US.
Large population-based retrospective
diabetes compared with 12% of hormone-naïve men.
series have demonstrated an increased risk for fracture in men who
Although the cause of increased fracture risk is due also
There are conflicting data on the impact of ADT on lipid profile—some to greater fall risk secondary to metastatic disease and treatment-related
studies have shown elevated low-density lipoprotein (LDL) and triglycerides,
frailty, decreased bone density from prolonged androgen suppression is
while others found no difference—but there is consistency in increased total certainly a major contributor. It is well accepted that hip fractures in the
cholesterol and high-density lipoprotein (HDL) across studies.
Due to the elderly affect survival; similarly, aside from the obvious associated
observed increases in HDL,
it is not entirely clear how the overall change morbidity, skeletal fractures in men with prostate cancer have also been
in lipid profile alone affects cardiovascular disease. Nonetheless, the shown to increase mortality.
constellation of these physiological changes comprises the metabolic
syndrome, which is associated with increased risk for cardiovascular disease There is some evidence that the use of ADT may be detrimental to survival
In a cross-sectional study, 55% men who had received more (see Figure 1). A post hoc subset analysis of the D’Amico trial suggested
than 12 months of ADT met the criteria for metabolic syndrome compared that in patients with moderate to severe comorbidity the addition of ADT
with 20–22% in the non-ADT and control groups.
decreased OS, with eight-year estimates of 54 versus 25%, although this
58 US ONCOLOGY
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