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Report of an encouraging outcome of a
trial combining "Taxotere" with Vitamin D (1,25-dihydroxyvitamin D3)
(February 2003)
The outcome of many recent chemotherapy
trials has in general produced quite similar results. However, in the
January 2003 issue of the Journal of Clinical Oncology, pp 123-128, Dr.
Beer and colleagues from the Oregon Health & Sciences University report
results of their efforts to improve outcome in their article: "Weekly High
Dose Calcitriol and Doxetaxel in Metastatic Androgen-Independent Prostate
Cancer". Their study involved 37 men with progressive PC (increasing
metastatic disease or rising PSA or worsening pain) treated with standard
dose doxetaxel ("Taxotere") at 36 mg/m2 weekly six times in an eight week
cycle accompanied by standard Decadron supplement. The novel feature was
the addition of one day of calcitriol (Roche,"Rocaltrol") at the high dose
of 0.5 micrograms/ kilogram body weight divided into four doses on the day
prior to chemotherapy. Results: 81% of men achieved a >50% decrease in PSA
and in 27 the fall was greater than 75%. Eight of 15 men with measurable
disease had partial responses; the median time to progression was 11.4
months; and the median survival was l9.5 months. Survival at one year was
89%.
Why Vitamin D? Calcitriol is 1,25-dihydroxyvitamin D3 (not standard
vitamin pill vitamin D). It is the active form of the vitamin. The kidney
is the site where other forms of oral vitamin D and the vitamin D that is
generated in our skin by sunlight are activated into the functional
molecule. Nephrologists are familiar with this agent and supplement kidney
dialysis patients with 0.25 - 0.50 micrograms daily to maintain calcium
balance and bone density. "High dose" in this study meant that a man of
160 pounds would get 35 micrograms once every weekly cycle. Underlying the
design of the Beer study is the emerging body of evidence that signaling
through the vitamin D receptor (the natural ligand for calcitriol) retards
proliferation of PC cells, enhances chemotherapy cytotoxicity, and
facilitates apoptosis (programmed cell death). There is considerable
evidence mounting that variations in the gene (polymorphisms) that codes
for the vitamin D receptor confer different degrees of susceptibility to
PC, and that this consequence may be operative in individual cases or even
on the racial level. The administered calcitriol remains in the blood for
several days and is therefore present during the highest period of
doxetaxol serum concentration. The side effect of calcitriol in this study
was three instances of mild, transient hypercalcemia.
Do the docetaxol-high dose calcitriol study results represent an
improvement over prior chemotherapies? The conclusion of the report calls
the results "promising" and indicates that a placebo-controlled,
double-blinded, randomized comparison of their regimen vs. doxetaxol alone
is already underway.
However, what are the reported results of "standard" chemotherapy - that
is: mitoxanthrone/prednisone, a taxane (either Taxol or Taxotere) with or
without estramustine ("Emcyt")? In his article Dr. Beer references results
of his own prior study of docetaxol (36 mg/m2, 6 weeks out of 8/cycle) and
results of a second similar study and two others dosing the chemotherapy
at 75 mg/m2 every 3 weeks. Collectively, they show a median fall of PSA of
42%, 28% partial responses, time to progression of 4.6-5.1 months, and
survival of 9.0-9.2 months. Other studies report somewhat better results.
The article that ushered in the recent era of PC chemotherapy,
"Hydrocortisone with or without mitoxanthrone in men with
hormone-refractory prostate cancer" (Journal of Clinical Oncology 1999
Aug; 17(8):2506-13) showed an overall survival of 12.3 months of M+H vs.
12.6 months for hydrocortisone alone. Quality of life issues favoring M+H
was the basis for the FDA's approval of mitoxanthrone in the treatment of
PC. In CANCER 2002 March:1457-65 Carducci reported a docetaxol/estramustine
trial that showed that 45% of men had a >50% fall in PSA, a median
duration of response of 4 months, and a median survival of 13.5 months. At
this time there is no consensus regarding the dose of estramustine, and
some researcher question whether it's a necessary ingredient considering
its toxcitities. If the 12.6 months survival in the hydrocortisone alone
arm of the M+H vs. H study is taken as a baseline, then all current
varieties of chemotherapy treatments fail to show a significant survival
advantage compared to H alone. That is why Dr. Beer and his group find
"promise" in the median survival of l9.5 month in their study and hope
that it can be confirmed in a larger study.
Bottom Line: The search for more effective chemotherapies in PC is being
actively pursued.
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