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Food
For Thought - Keep An Open Mind (December 2003)
In the face of the
rising PSA of androgen insensitivity clinicians customarily continue
Lupron - almost indefinitely. Is this done only in keeping with
"custom"? Why do we do this? Is there any biologic rationale or
established evidence supporting this practice? True, prostate cancer is
always heterogeneous with respect to its androgen sensitive and
insensitive components, so possibly the Lupron continues to address with
diminishing usefulness the diminishing number of androgen sensitive
cells. The only study I am aware of that focused on this issue (and I
can't find the reference) was a SWOG study years ago that showed a four
month survival benefit for continuing androgen suppression in this
clinical situation. In the November 5 JNCI an editorial, "Playing the
Old Piano: Another Tune for Endocrine Therapy" and a related article
probe deeply into this area, with a focus in this case on breast cancer,
and emerge with a related provocative biologic insight.
The emerging biologic
understanding of prostate cancer's sister endocrine disease, breast
cancer, is always relevant to our concepts about prostatic cancer. In
each of these diseases the phases of progression and their underlying
mechanisms are parallel. So the work of Craig Jordan, PhD, DSc, the guru
of Tamoxifen, reported in this journal, is poignant.
The essence of the
study is Jordan's observation that in the hormone deprived environment
(resulting for example, from oophorectomy or Tamoxifen) after the
initial cellular apopotic wave, the remaining once-hormone sensitive
cells reset and lower their threshold for hormone sensitivity. At this
point in our discussion, a historical fact about prior breast cancer
therapy is relevant. Ever since 1896 an option of treatment of
metastatic breast cancer has been oophorectomy (analogous to using
Lupron), and when the disease escaped from this state of hormone
deprivation, paradoxically, diethylstilbesterol (DES) at the "industrial
strength" dose of 15 mg had a good record of reclaiming disease control,
again bringing about apoptosis. "Paradoxical" because initially it was
the absence of estrogen that led to the first response, and that
a second wave of apoptosis should result from reintroduction of estrogen
seemed counter intuitive. The new twist in Jordan's work is that he has
established that in the "hypersensitive to estrogen" state that
developes in the estrogen deprived cells, even a small amounts of
estrogen - actually the amount normally present in a woman's circulation
- is sufficient to effect the new round of cell death! "We have
confirmed and extended our original observation that low concentrations
of estrogen shift the survival of SERM-resistent breast cancer cells by
initiating apoptosis" ...[SERM = Tamoxifen; i.e."resistant" because
cells achieve growth potential despite estrogen deprivation]..."Overall,
these data ... suggest that it is possible for a patient's own estrogen
to act as an anticancer agent in SERM-resistent breast cancer."
Of what relevance is
this data for the management of prostate cancer? It certainly argues for
a reexamination of the custom of continuing Lupron in the face of
"androgen insensitivity". And a protocol at Memorial Sloan Kettering
(MSKCC-99115) has picked up on this idea with a "Phase I Study of
Testosterone in Patients with Progressive Androgen-Independednt Prostate
Cancer", thus paralleling the early use of DES in breast cancer
management. In this study Lupron is continued, but daily testosterone
patches of increasing strength are applied to reintroduce testosterone
in a controlled fashion. The proof of the pudding will be in the eating.
Bottom Line:
Food for thought - but not quite fully cooked at this point.
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