Download Phase I/II Study of 19-nor-1A-25-Dihydroxyvitamin D2 (Paricalcitol

Cancer Therapy: Clinical
Phase I/II Study of 19-nor-1A-25-Dihydroxyvitamin D2 (Paricalcitol)
in Advanced, Androgen-Insensitive Prostate Cancer
Gary G. Schwartz,1 M. Craig Hall,2 Diana Stindt,3 Suzanne Patton,6 James Lovato,4 and Frank M. Torti1,5
Abstract
Purpose: We assessed the safety and efficacy of the vitamin D analogue, 19-nor-1a-25dihydroxyvitamin D2 (paricalcitol), in patients with androgen-independent prostate cancer.
Experimental Design: Patients received paricalcitol i.v. three times per week on an escalating
dose of 5 to 25 Ag (3-15 Ag/m2). The primary end point was prostate-specific antigen (PSA)
response. Secondary end points were characterization of toxicity in this population, changes in
serum parathyroid hormone (PTH), and survival.
Results: A total of 18 patients were enrolled. No patient showed a sustained 50% drop in
serum PSA, despite several large declines in PSA (e.g., 1,300 ng/mL). Paricalcitol was well
tolerated. One instance of significant hypercalcemia, a serum calcium of 14.3 mg/dL, was
observed at the highest dose (25 Ag). At entry into the study, seven (41%) of the patients
had elevated serum levels of PTH, which were significantly reduced by paricalcitol. Higher
levels of serum PTH at study entry were significantly and negatively associated with survival
(P < 0.01).
Conclusion: No objective responses were seen in the primary end point. However, elevated
serum levels of PTH, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated PTH is associated with increased cardiovascular and skeletal morbidity,
including an increased risk for pathologic fracture, further evaluation of paricalcitol in the
reduction of skeletal morbidity in advanced prostate cancer is warranted.
Prostate cancer is the most prevalent (nonskin) cancer among
American men and the second most fatal, accounting for
>30,000 deaths in 2005 (1). For men with advanced disease,
the mainstay of prostate cancer therapy is androgen withdrawal. Although androgen withdrawal is usually effective in
lowering prostate-specific antigen (PSA) in men with prostate
cancer, in men with metastatic disease, the duration of response
is brief (about 14-18 months), and androgen-independent
prostate cancer (AIPC) supervenes in virtually all treated men.
The median survival once AIPC develops is 12 to 18 months.
Although recent clinical trials in AIPC have shown a survival
benefit for docetaxel-based chemotherapy, the benefit is
modest (about 2 months; refs. 2, 3). Thus, new therapies for
AIPC are urgently needed (4, 5).
Considerable attention has focused on the role of vitamin D
in prostate cancer, stemming from the observation by Schwartz
Authors’ Affiliations: Depar tments of 1Cancer Biology, 2 Urology, and
3
Hematology/Oncology; 4Section on Biostatistics, Department of Public Health
Sciences; and 5Comprehensive Cancer Center of Wake Forest University, WinstonSalem, North Carolina; and 6Northwest Georgia Oncology Centers, Douglasville,
Georgia
Received 6/9/05; revised 9/15/05; accepted 9/26/05.
Grant support: Abbott Laboratories, Abbott Park, IL investigator-initiated grant.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Frank M.Torti, Comprehensive Cancer Center,Wake Forest
University, Medical Center Boulevard,Winston-Salem, NC 27157. Phone: 336-7167971; Fax: 336-716-0293; E-mail: ftorti@ wfubmc.edu.
F 2005 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-05-1237
Clin Cancer Res 2005;11(24) December 15, 2005
and Hanchette that mortality rates from prostate cancer are
inversely related to levels of UV radiation, the major source of
vitamin D (6). Vitamin D is synthesized in response to sunlight
and undergoes hydroxylation in the liver to 25-hydroxyvitamin
D (calcidiol) and then in the kidney to form 1,25-dihydroxyvitamin D (calcitriol), the hormonal form of vitamin D.
Extensive research has shown that prostate cells, including
prostate cancer cells, express specific receptors (VDR) for 1,25dihydroxyvitamin D. When bound to the VDR, 1,25-dihydroxyvitamin D regulates >60 genes that exert prodifferentiating,
antiproliferative and antimetastatic effects on prostate cells,
including effects on cell cycle. These data support the use of
calcitriol and analogues as therapeutic agents in prostate cancer
(see refs. 7, 8 for reviews).
Promising preclinical evaluations of calcitriol and analogues
have appeared in prostate cancer animal models (9, 10). Several
clinical trials of calcitriol and analogues in AIPC have been
reported, including those using calcitriol (11, 12) and the
prodrug, 1a-hydroxyvitamin D2 (doxercalciferol) as monotherapy (13), as well as calcitriol in combination with other agents
(e.g., docetaxel, zoledronate, and dexamethasone; ref. 14).
Recently, Beer et al. reported an 81% response rate for the
combination of calcitriol and docetaxel in metastatic prostate
cancer versus an expected response of 40% to 50% for docetaxel
alone (15).
The principal toxicity of calcitriol as an anticancer drug is
hypercalcemia. The calcitriol analogue, 19-nor-1a-25-dihydroxyvitamin D2 (paricalcitol, Zemplar), was approved by the Food
and Drug Administration in 1998 for the prevention and
treatment of secondary hyperparathyroidism associated with
chronic renal failure. In patients with chronic renal failure,
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Paricalcitol and Advanced Prostate Cancer
paricalcitol is three to four times less calcemic than 1,25dihydroxyvitamin D (see ref. 16 for a review). We recently
reported that paricalcitol was as effective as 1,25-dihydroxyvitamin D in transactivating the prostatic VDR and in inhibiting
the growth of prostate cancer cell lines and primary cultures of
prostate cancer cells in vitro (17). These findings served as the
basis for the exploration of paricalcitol in AIPC.
If two or more patients on a given dose level experienced a grade
4 toxicity, the study would be stopped. If the true probability of a
dose-limiting toxicity at one of the first two dose levels was 50% or
70%, the probability of stopping at that dose was 83% or 97%,
respectively. If the true probability of a dose-limiting toxicity at one
of the last three dose levels was 50% or 70%, the probability of
stopping at that dose was 89% or 99%, respectively. Survival analysis
employed an intent-to-treat basis using the Kaplan-Meier method.
Results
Materials and Methods
Eligibility criteria. Eligible patients for this phase I/II trial were
men with confirmed adenocarcinoma of the prostate, advanced,
androgen-insensitive disease; an Eastern Cooperative Oncology
Group performance status of 1 to 2; and a PSA > 10 ng/mL. This
was a dose escalation trial, with paricalcitol doses starting at 5.0 Ag
(3.0 Ag/m2) i.v. thrice per week and escalating at 5.0-Ag intervals to
25.0 Ag (15.0 Ag/m2). The protocol was approved by the Institutional
Review Board at Wake Forest University, and all patients signed
informed consent forms before registration.
Toxicity was assessed after 4 weeks. If no grade 4 toxicities were
observed, treatment continued for up to 12 weeks. At this time, if
disease was stable or there was a PSA response, the patient continued
on the same dose. If a patient progressed, the dose was escalated to
the next higher level. Dose escalation was not allowed until
resolution of any grade 3 toxicity. No more than one dose escalation
was permitted per patient.
Drug formulation. Paricalcitol (paricalcitol injection) is a calcitriol
analogue whose chemical designation is 19-nor-1a,3h,25-trihydroxy9,10-secoergosta-5(Z),7(E),22(E)-triene. It is available as a sterile,
aqueous solution for i.v. injection and was provided courtesy Abbott
Laboratories (Abbott Park, IL).
Serology. Pretreatment serum levels of 25-hydroxyvitamin D (a
measure of vitamin D sufficiency) were determined at study entry.
Measurements of serum calcium, phosphorus, and creatinine were
obtained after 2 weeks of treatment. Serum calcium, phosphorus,
and PSA were measured after 4, 8, and 12 weeks. Serum parathyroid
hormone (PTH) was measured at baseline and after 12 weeks. Serum
alkaline phosphatase and the calcium-phosphorus (Ca P) product,
corrected for serum albumin, was obtained at baseline and after 12
weeks of treatment.
Serum calcium and phosphorus was measured with the ADVIA 1650
system. The measurements of phosphorus are based on Daly and
Ertinghausen procedure, which relies upon the formation of a UVabsorbing complex between phosphorus and molybdate. The calcium
method is based on the work of Gitelman, in which calcium ions form
a violet complex in an alkaline medium. Measurement of intact PTH
employed the immunometric assay and used the Immulite Analyzer.
PSA was measured using the Bayer Immuno 1 System, using a sandwich
immunoassay. 25-Hydroxyvitamin D was measured by RIA.
Outcome assessment. The primary outcome was PSA response,
defined as a 50% decrease in PSA with confirmatory consecutive
measurement at least 4 weeks apart. PSA was assessed monthly.
Secondary outcomes were changes in intact PTH, evaluation of hypercalcemia, Ca P product, other toxicities, and survival. Progression
was defined as a 50% increase in serum PSA or the appearance of a
new metastatic lesion at any site.
Statistical considerations. The phase I/II study was designed as a
dose escalation study to determine the maximally tolerated dose
of paricalcitol in these patients. Three patients were to be treated
initially at each of the first two dose levels, which approximate the
initial dose of paricalcitol used in the treatment of patients with
secondary hyperparathyroid disease. Accrual of an additional three
patients to a given dose level was planned if one of three patients at
that dose level experienced a grade 4 toxicity. Six patients were to be
treated at each of the last three dose levels to explore doses closer to,
and beyond, the maximal doses previously reported.
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Patient characteristics. Eighteen men were recruited between
January 2001 and May 2002. Pretreatment characteristics of the
patients are shown in Table 1.
Prior therapies. Three patients were treated initially with
prostatectomy; six were treated with primary radiation
therapy. Fifteen patients were treated with various forms of
hormonal therapy, including luprolide, bicalutamide, flutamide, nilutamide, and ketoconazole/prednsione. Six patients
had been treated with orchiectomy. Five patients received
prior treatment with chemotherapy (either single-agent
doxorubicin or combination therapy with vineralbine tartrate,
doxorubicin, and prednisone). All but two patients had
received more than one type of prior therapy, and most men
had been treated with multiple therapies. No patient had
received prior therapy with bisphosphonates.
Toxicity. Eleven patients were dose escalated, for a total of
29 cycles delivered. Intravenous paricalcitol was well tolerated.
In general, adverse side effects were mild and/or minimal.
Mild nausea was reported by eight patients. Vomiting was
noted by two patients and was also mild. One patient
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Table 1. Summary of patient characteristics
at enrollment
Patient characteristics
No. patients
Age (y), median (range)
Race, n (%)
Caucasian
African American
ECOG performance status, n (%)
0
1
PSA (ng/mL), n = 18
PTH (pg/mL), n = 17
Patients with bone metastases, n (%)
Patients with elevated PTH, n (%)
Alkaline phosphatase (units/L), n = 17
Calcium (albumin corrected, mg/d), n = 18
Albumin (g/dL), n = 18
Phosphorus (mg/dL), n = 18
Creatinine (mg/dL), n = 17
25-Hydroxyvitamin D (ng/mL), n = 16
Ca P (mg2/dL2, corrected), n = 18
18
74.4 (51-83)
15 (83)
3 (17)
16 (89)
2 (11)
119 (4-2,047)*
69 (32-396)
14 (78)
7 (41)
118 (72-4,302)
9.4 (8.1-10.2)
4.1 (3.5-4.4)
3.5 (2.6-3.7)
1.3 (1-1.7)
19.5 (8-34)
31.6 (25.6-36.7)
NOTE: Data are given as medians and ranges.
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
*One patient, whose PSA at entry was <10, was entered into the trial in error.
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experienced a grade 2 photosensitive rash that was considered to be drug related during cycle 1, week 6, of the 15-Ag
dose. This resolved without intervention. Another patient had
grade 2 neutropenia that was possibly drug related.
Other observed effects were considered by the investigators
not to be drug related. These include grade 4 thrombocytopenia in a patient who had undergone right hemicolectomy
3 days previously and subsequently died, grade 3 pneumonia
after 3 doses of the 25-Ag dose in a patient who had a prior
history of pneumonia, grade 3 alkaline phosphatase in four
patients that was related to their advanced prostate cancer,
and grade 3 cardiac dysrhythmia (atrial fibrillation) in one
patient with a history of chronic atrial fibrillation on the 10Ag dose after undergoing right hip replacement. This occurred
post-surgically 4 days after the last dose of paricalcitol. This
same patient had grade 3 leg edema that was considered to
be related to his advanced cancer and hip surgery. Eleven
patients reported mild dizziness and weakness. One patient
reported mild flu-like symptoms. Two patients experienced
urinary tract infections.
Prostate-specific antigen response. PSA continued to increase
in most men. However, one patient experienced a minimal
increase in PSA during 3 months of treatment (27-33 ng/mL),
and a second patient showed a decline in PSA from 2,136 to
1,648 (23% decline on the 10-Ag dose). A third patient
experienced a large decline in PSA from 2,837 to 1,326 ng/mL
(53% decline on his second dose level of 15 Ag) that was not
sustained at the 50% level. This patient had previously shown a
decline in PSA from 2,047 to 1,575 (23%) on the first dose
level of 10 Ag.
Calcium. Hypocalcemia was defined as any value below the
laboratory reference value of 8.5 mg/dL, and hypercalcemia as
any value of >10.5 mg/dL. Serum calcium was normalized to a
serum albumin concentration of 4.0 g/dL for any patient with
a serum albumin of <4.0 g/dL.
Four patients developed elevations in serum calcium during
treatment. Two of these had one measurement that was mildly
elevated (10.6 and 11.1 mg/dL) at the 5- and 20-Ag doses,
respectively, which returned to normal levels. Another patient
showed a serum calcium of 11.5 and 11.7 mg/dL at the 15- and
20-Ag doses. A fourth developed hypercalcemia at the 20-Ag
dose, reaching a maximum of 14.3 mg/dL at the 25-Ag dose,
when the patient came off study due to disease progression.
Conversely, 3 of 18 (17%) patients showed at least one
episode of hypocalcemia with values of 8.1, 8.4, and 8.3 mg/dL
at the 10-, 15-, and 20-Ag doses.
Phosphorus. The lower and upper laboratory limits for
phosphorus were 2.7 and 4.5 mg/dL. Paricalcitol had little
effect on serum phosphorus levels, from a mean of 3.38 mg/
dL pretreatment to 3.39 mg/dL posttreatment. Only two
instances of mild hyperphosphatemia were observed during
the course of the study, in two patients, with serum levels of
4.6 and 5.0 mg/dL at the 15- and 25-Ag doses, respectively.
Conversely, 5 of 18 (28%) patients developed at least one
instance of hypophosphatemia, with the lowest serum
phosphorus recorded being 1.9 mg/dL. One man who
developed hypophosphatemia was mildly hypophosphatemic
at study entry (2.6 mg/dL).
25-Hydroxyvitamin D. The laboratory reference range for
25-hydroxyvitamin D was 10 to 68 ng/mL. Serum baseline
levels of 25-hydroxyvitamin D were normal in the majority
Clin Cancer Res 2005;11(24) December 15, 2005
Fig. 1. Pretreatment and posttreatment serum PTH in men with advanced prostate
cancer.The dotted line shows the cut point for normal serum initial PTH (72 pg/mL).
Posttreatment PTH levels were available after 12 weeks in 11men; for five men,
posttreatment values were obtained after 2 to 6 weeks. The median PTH at entry
(pretreatment) was 69 pg/mL and was 33.5 pg/mL posttreatment (P < 0.0004).
(14 of 16, 88%) of men. Two men showed borderline
hypovitaminosis D, with serum levels of 8 and 9 ng/mL.
Calcium-phosphorus product. The (albumin corrected) Ca P
product was calculated for the 12 patients who remained on
study for at least 12 weeks. No clinically significant elevations
were observed. Paricalcitol had little effect on the Ca P
product: the median (and range) values pretreatment and
posttreatment were 31.6 (25.6-36.7) and 30.0 (19.1-49.1),
respectively.
Parathyroid hormone. The lower and upper limits for intact
PTH were 8 and 72 pg/mL. Paricalcitol significantly reduced
serum PTH. The median PTH at entry into the study was
69 pg/mL (range, 3-396); the median posttreatment was
33.5 pg/mL (range, 5-237; P <0.0004, paired t test). Of the
17 men with baseline PTH values, seven (41%) had elevated
PTH levels. An additional two men presented with PTH levels
that were borderline (both 69 pg/mL). One patient, whose
duration on the trial was only 4 weeks, showed a decline in
PTH from 396 to 237 pg/mL (40%) after 2 weeks of therapy. Of
the seven men with abnormal levels, five returned to normal.
Four of the five normalizations occurred while the men were on
the first dose (5, 10, 15, and 20 Ag); the fifth normalization
occurred on the second dose (15 Ag). Two men who had
normal baseline PTH values developed elevated serum PTH
levels subsequently; one on the 5-Ag dose, his first dose and one
on the 10-Ag dose, his second dose.
The relationship between pretreatment and posttreatment
PTH is shown in Fig. 1.
Alkaline phosphatase. The upper laboratory limit for alkaline
phosphates was 110 units/L. Pretreatment and posttreatment
values for alkaline phosphatase were available for 17 of 18
patients. At entry into the trial, alkaline phosphatase was
elevated in approximately half of the patients (median = 118),
reflecting the presence of bony metastases. Alkaline phosphatase levels continued to increase in 11 of 18 patients (median =
119; range, 27-2,419). They showed no change in one and
declined in five patients.
Survival. As of August 10, 2005, all but one patient had
expired. The median survival was 9.0 months with a 95%
confidence interval of 8.5 to 22.2 months. The cause of death in
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Paricalcitol and Advanced Prostate Cancer
Fig. 2. Kaplan-Meier plot of survival for 17 patients as a function of initial PTH.
The estimated median survivals for baseline PTH of 3, 70, and 400 (the minimum,
median, and maximum baseline values in our trial) are 21. 2, 10.7, and 4.0 months,
respectively.
these men was prostate cancer (n = 15), myocardial infarction
(n = 1), and post-surgical decline, following surgery for repair
of a perforated bowel (n = 1).
The survival curve as a function of initial PTH is shown in
Fig. 2. For every 25 pg/mL increase in PTH, the hazard increases
22% (95% confidence interval for hazard ratio, 1.03-1.43; P =
0.01, log-rank test). The estimated median survivals for baseline
PTH of 3, 70, and 400 (which represent the minimum, median,
and maximum baseline values in our trial) are 21.2, 10.7, and
4.0 months, respectively.
To determine whether the relationship between PTH and
survival was independent of the extent of disease, we used
serum PSA as a marker of extent of disease and did survival
analyses using a Cox regression model that included both
PSA and PTH variables in the model (18). In this model, the
relationship between survival and initial PSA was not
significant (P = 0.97, Wald test), but the effect of PTH
remained significant (P = 0.02, Wald test). This indicates that
the survival effect associated with PTH was present even after
adjustment for disease severity.
Discussion
No patient in this trial showed a sustained 50% decrease in
PSA, the primary end point. However, one patient, while on the
15-Ag dose, experienced a large decline in PSA (2,837-1,326 ng/
mL, 53%). This rose to 1,500 ng/mL on the next determination
(a 47% decline), narrowly missing the criterion for a sustained
decline. The same patient, while on the 10-Ag dose, showed a
drop in PSA from 2,047 to 1,575 (23%). Similar findings were
reported by Osborn et al. (11) for 13 patients in the first clinical
trial of oral calcitriol in AIPC, and for 22 patients treated with a
high-dose formulation of oral calcitriol reported by Beer et al.
(12). No patient in these studies showed a sustained 50%
decline in PSA.
The maximally tolerated dose for paricalcitol was not reached
in this study, although patients were treated with paricalcitol at
doses 50% higher than those previously reported in the literature
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(i.e., 25 versus 16.8 Ag; ref. 19). These doses were well tolerated.
Eight (46%) patients reported mild nausea, consistent with
reports of nausea in patients with end-stage renal disease treated
with paricalcitol (20). The one patient who developed a grade
3 toxicity and a serum calcium of 14.3 mg/dL had a blocked
nephrostomy tube the day before his blood draw. It is thus
possible that his decreased excretion of urinary calcium
contributed to his elevated serum calcium. Conversely, two
men were hypocalcemic at study entry, with serum calciums of
8.1 and 8.2 mg/dL. Two other patients developed at least one
episode of hypocalcemia during their treatment. The hypocalcemia was apparently not due to hypoalbuminemia, as no
patient had serum albumin levels below the normal laboratory
range (3.2 g/dL). Similarly, although two patients showed
elevations in serum phosphorus, hypophosphatemia was more
common, with six patients showing at least one instance of
hypophosphatemia during the course of the study.
Few significant elevations in serum calcium in these men
were observed. Similarly, no significant elevations in Ca P
product were seen. The current recommendation for the Ca P
product in chronic kidney disease and in the dialysis
population is V55 mg2/dL2 (21). Our results were well below
this limit: the median posttreatment Ca P product was 30.0,
and the highest observed value was 49. It is likely that the
tendency of metastatic prostate cancer to be associated with
hypocalcemia rather than hypercalcemia increases the therapeutic window for calcitriol analogues in this population.
Clinical trials in the dialysis population have shown that
paricalcitol reduces serum levels of alkaline phosphatase,
indicating a reduction in bone remodeling (22). Pretreatment
and 12 week posttreatment levels of alkaline phosphatase were
available for 17 of our patients. One showed no change in
alkaline phosphatase levels, 11 of 17 (65%) showed increases,
and 5 of 17 (29%) showed declines. This suggests that
paricalcitol may reduce bone remodeling in some patients
even in the presence of rising PSA.
In patients with chronic renal failure, the peak serum
concentration of paricalcitol was 4.4 F 1.6 10 9 mol/L after
a dose of 0.24 Ag/kg (16.8 Ag). This is the recommended
maximum dose in the treatment of secondary hyperparathyroidism (18). In our trial, considerably higher doses did not
result in frequent hypercalcemia or in an elevated Ca P
product. Our previous laboratory studies showed a 20%
inhibition in the proliferation of primary cultures of prostate
cancer cells exposed to paricalcitol at 10 9 mol/L, suggesting
that some inhibition of prostate cell growth in vivo might be
achievable at these doses (17). Because the maximally tolerated
dose was not reached in this study, further study of paricalcitol
at higher doses would be valuable.
Upon entry into the study, elevations in serum PTH were
found in 7 of 17 (41%) men; an additional two (12%) had
PTH levels that were borderline. Treatment with paricalcitol
significantly reduced PTH in these men. Low serum calcium
and high serum PTH are common but often unrecognized
features of advanced prostate cancer. For example, in a series of
75 prostate cancer patients with bony metastases, hypocalcemia
occurred during the course of the disease in 31% (23). Murray
et al. reported a series of 146 unselected patients with advanced
prostate cancer (24). The prevalence of elevated PTH in that
series was 34% and was >50% in patients with bony metastases.
These findings are in keeping with the ‘‘hungry tumor
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phenomenon’’ (25) or ‘‘bone hunger syndrome’’ (26), in which
osteoblastic metastases cause increased deposition of calcium
into bone. The resulting hypocalcemia causes an elevation in
serum PTH (i.e., secondary hyperparathyroidism; ref. 27).
Chronic kidney disease and/or vitamin D deficiency are
common causes of secondary hyperparathyroidism. However,
in the majority of our patients, serum levels of creatinine and of
25-hydroxyvitamin D were within the normal laboratory ranges
(88% and 83%, respectively). This suggests that the ‘‘hungry
bone’’ and not kidney disease or vitamin D deficiency was the
predominant cause of the elevated PTH.
Although elevated serum PTH that is associated with vitamin
D deficiency may be treated with supplemental vitamin D and/or
calcium (21), elevated PTH caused by hungry bone may be
refractory to these first-line therapies (e.g., ref. 28). Vitamin D
deficiency traditionally was defined as 25-hydroxyvitamin D V
10 ng/mL (25 nmol/L), as this value is associated with rickets in
children and osteomalacia in adults (29). Recently, the term
vitamin D insufficiency (synonyms, mild, moderate vitamin D
deficiency; 10-20 and 5-10 ng/mL, respectively) has been used to
describe less severe deficiency that is associated with elevated
serum PTH. A value of 20 ng/mL (50 nmol/L) is commonly used
to define vitamin D insufficiency as this is the threshold above
which serum PTH levels are not decreased by vitamin D
supplements (30).
The median 25-hydroxyvitamin D in our study was 19.5 ng/
mL. Thus, vitamin D supplements would be expected to lower
PTH in only half of these patients. Moreover, the magnitude of
the PTH elevation caused by mild vitamin D deficiency is <15%
(30). Thus, vitamin D supplements would be expected to have
a modest effect in PTH reduction and only in those patients
with mild vitamin D deficiency.
To our knowledge, the only published attempt to reduce
PTH in patients with advanced prostate cancer with calcium
supplements was that of Murray et al. (24). These authors
treated 32 patients with elevated PTH with oral calcium
(600 mg Caltrate twice daily, increasing to 1,200 mg). PTH
levels fell initially but returned to pretreatment levels by 3
months, despite continuing supplementation. These authors
hypothesized that large amounts of calcium may be needed
to significantly raise serum calcium and thereby depress
serum PTH in this population. Our data indicate that the
elevated serum PTH in men with advanced prostate cancer
was effectively depressed by paricalcitol. An important
potential advantage of paricalcitol in this setting is that
paricalcitol is known to inhibit the proliferation of prostate
cancer cells.
Elevated serum levels of PTH are associated with increased
mortality from cardiovascular disease in the dialysis population
(31). Moreover, recent literature suggests that elevated serum
levels of PTH may have additional deleterious effects in
advanced prostate cancer. For example, in vitro, PTH increases
the proliferation of androgen-insensitive DU-145 human
prostate cancer cells and increases chemotaxis in three human
prostate cancer cell lines (32). In vivo, the incidence of skeletal
metastatic foci was significantly increased in mice treated with
PTH versus mice treated with saline control (33). In men
with prostate cancer (without evidence of bone metastases),
the infusion of PTH increased serum and urinary levels of
N-telopeptide (34), a marker of bone resorption that has been
correlated prospectively with the progression of bony metastases (35) and with the frequency of skeletal complications (36).
Finally, our data indicate that initial serum levels of PTH were
negatively and significantly associated with survival, and this
effect was independent of disease severity as measured by PSA.
Together, these studies support the hypothesis that PTH
increases the proliferation and metastasis of prostate cancer
cells and suggests the desirability of PTH suppression in
prostate cancer patients with elevated PTH.
Previous trials of calcitriol and analogues in prostate cancer
have focused either on PSA response and/or survival. To our
knowledge, this is the first trial that specifically addressed PTH.
We observed that paricalcitol, which was designed to suppress
PTH in patients with chronic renal disease, significantly
suppressed PTH in men with advanced prostate cancer.
Whether PTH suppression in this population is associated with
increased survival and/or improved quality of life are important
issues that could be addressed by future clinical trials.
In prostate cancer cells in vitro, we showed previously that
paricalcitol acts synergistically with ionizing radiation to
increase the efficacy of ionizing radiation to induce prostate
cancer cell kill at therapeutically relevant doses (1-2 Gy; ref. 37).
Importantly, paricalcitol did not induce significant radiosensitization of normal prostate epithelial cells. This suggests that
paricalcitol also may have use as an adjuvant to ionizing
radiation. The capsule formulation of paricalcitol, which has
recently been approved for the prevention and treatment of
secondary hyperparathyroidism in stage 3 and 4 chronic
kidney disease patients, should facilitate clinical investigations
of paricalcitol in prostate cancer.
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