Objectives: The existing luteinizing hormone-releasing hormone (LHRH) analo
gs have been the preferred method of inducing androgen deprivation for pros
tate cancer for over a decade. These agents are well known to cause a surge
in serum testosterone levels during the first week of therapy. However, th
ere are wide discrepancies in reports of the frequency and severity of acut
e clinical progression or clinical flare that might result from the testost
erone surge. Also, there is not a clear consensus as to whether antiandroge
ns should be routinely given to all patients during the first month of LHRH
therapy to prevent flare responses.
Methods: Clinical trials involving LHRH analog therapy for prostate cancer
were reviewed, and the frequency of clinical flare responses noted. Particu
lar attention was given to the kinds of clinical problems associated with t
he flare response. The use of LHRH analog therapy in treatment of patients
with prostate cancer for indications other than overt metastatic disease is
discussed, because this is becoming a much more common use of these agents
. This article analyzes 2 placebo-controlled, double-blind trials testing t
he effectiveness of existing antiandrogens in ameliorating flare responses.
Results: The use of LHRH analogs for patients with stage D2 disease can be
associated with clinical flare in approximately 10% of D2 patients. In addi
tion to bone pain, cord compression, and bladder outlet obstruction, anothe
r potentially severe side effect is cardiovascular risk arising presumably
from hypercoagulability associated with a rapid increase in tumor burden. I
n clinical series involving D2 patients, the frequency of clinical flare gr
eatly varies, probably because of the level of scrutiny of the investigator
and/or the prostate-cancer tumor burden present at the initiation of thera
py. Concomitant antiandrogen therapy reduces, but does not totally eliminat
e, the flare responses in patients at high risk for flare. Treating prostat
e cancer in the DO stage or in the neoadjuvant setting will result in bioch
emical evidence of testosterone surge, but these patients are at very littl
e risk for clinical flare responses.
Conclusions: There is a wide variation in the reported frequency of clinica
l flare responses from LHRH analogs during the initial treatment of patient
s with stage D2 disease. The risk-to-benefit ratio, especially in patients
with symptomatic bone metastasis, would dictate routine use of antiandrogen
therapy for the first month of LHRH analog treatment. For patients at risk
for cord compression, other means of ablating testosterone might be consid
ered, such as ketoconazole, orchiectomy, or LHRH antagonists. Clinical flar
e responses, as opposed to biochemical flare responses, are very rare durin
g LHRH analog therapy for stage DO disease and/or in the setting of neoadju
vant hormonal therapy.