Conrad P is a bag of bones just
waiting to break. The 70-year-old smoker is painfully
thin and has prostate cancer for which he's been given
gonadotrophin-releasing hormone (GnRH). Could his plight
get any worse? Well, yes — according to a study published
January 13 in the New England Journal of Medicine
the treatment he's on could literally be the last straw
that breaks the camel's back. The research pins the blame
for the dramatic rise of serious fracture risk in prostate
cancer patients squarely on unproven hormonal therapies.
Androgen deprivation therapies
like orchiectomy and treatment with GnRH agonists were
originally intended to improve survival in locally advanced
disease and to palliate metastases when used in conjunction
with radiation. But over the past decade, such treatments
are increasingly being used for patients with localized
disease, and even those who simply show a rise in prostate
specific antigen (PSA) after prostatectomy.
WHAT'S
THE HARM?
"The reasons for this increase may include demonstrated
efficacy in patients with locally advanced cancer, the
financial incentives to providers, and the urge, on
the part of physicians and patients, to do something
in the face of a rising PSA level," suggest the authors
of the latest study. "Our findings, along with those
of smaller clinical series, underscore that such treatment
is not benign."
University of Texas researchers
led by Dr Vahakn Shahinian analyzed the health records
of 50,613 men aged 66 or older who were diagnosed with
prostate cancer between 1992 and 1997. One group had
undergone either orchiectomy or treatment with GnRH
agonists within six months of their diagnosis; the other
had never received hormonal treatments for their cancer.
Fracture rates from the year prior
to diagnosis were compared to those in the period from
one to five years after diagnosis. While vulnerability
to fracture increased significantly in both groups,
it rose much faster in the androgen deprivation group.
Orchiectomy patients had the highest fracture risk —
1.54 times higher than those who hadn't taken hormonal
treatment. GnRH agonists were almost as bad for bones
when used frequently. Patients who received nine or
more doses of GnRH agonists faced a fracture risk 1.45
times higher than the control.
When only serious fractures requiring
hospitalization were considered, the negative effect
of hormonal treatment was even greater, though it tended
to be submerged by other factors in patients with many
comorbid conditions.
Overall, the researchers conclude
that about 3,000 additional fractures occur in the US
every year because of hormonal therapy. The risks would
be acceptable if we knew these treatments were saving
lives, the authors suggest, but we don't. The authors
stop short of calling for a halt to hormonal therapy
for localized disease or rising PSA, but, they say,
"the risk of fracture and other toxic effects should
therefore figure prominently in discussions between
physician and patient with regard to the decision to
initiate androgen-deprivation therapy."
CANADIAN
PERSPECTIVE ON PAIN
There is a potential solution, of course, in the form
of bisphosphonates to counteract bone damage. Bisphosphonates
have also been used extensively to palliate the pain
of bone metastases in prostate cancer, but not so much
in patients with less advanced disease. The Canadian
Coordinating Office for Health Technology Assessment
(CCOHTA) recently reviewed the evidence for bisphosphonates
on bone pain relief in cancer, and concluded that pamidronate,
zolendronate, clonodronate and etidronate were all about
equally effective.
But CCOHTA failed to consider bone
density and fracture risk or distinguish between different
cancer sites — bone damage tends to be most pronounced
for those with cancer at sites traditionally associated
with osteoporosis, such as the hip, spine and forearm.
It would be a pity if CCOHTA's conclusions should lead
formularies to conclude that one bisphosphonate is as
good as another.
THE
BETTER BISPHOSPHONATE
In fact, a 2003 study of pamidronate in the Journal
of Clinical Oncology found that the drug failed
to prevent fractures in bone-metastatic prostate cancer
patients. A 2002 Canadian-led study in the Journal
of the National Cancer Institute (JNCI), conversely,
found that zolendronate did reduce fracture risk in
a similar cohort of patients. These were patients who
had tried hormonal therapy without success.
The authors of that study felt
unable to recommend zolendronate as a standard therapy
in metastatic patients because despite the lower fracture
toll, it didn't reduce pain or prolong survival. But
patients with localized disease — or post-prostatectomy
patients who see their PSA rising — are not burdened
by pain, and have far better prospects for survival.
Now that we know these patients are at high risk of
fractures, it might be worth studying how they fare
with bisphosphonates.
Dr Ian Tannock, a University of
Toronto specialist, said that zolendronate would definitely
be more appropriate in early-stage patients whose bone
loss was due to hormonal therapy. "I think it's rather
a good drug for those patients. What bothered me about
the zolendronate research was that they were pushing
the dosages. I've seen good evidence that zolendronate
is protective against fracture at one dose every three
months. But researchers have been trying one dose per
three weeks, which pushes toxi-city way up and makes
the cost prohibitive."
NEJM Jan 13,
2005;352:154-64
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