In preclinical systems, calcitriol, the natural vitamin D receptor (VDR) ligand, has been found to demonstrate antiproliferative effects, although concentrations > 1 nM are required. Unlike daily dosing, weekly administration of oral calcitriol can safely achieve such blood calcitriol concentrations. This study sought to define the long-term toxicity of this regimen and measure its effect on serum prostate specific antigen (PSA) levels in patients with hormone-naïve prostate carcinoma.
Patients with a rising serum PSA after prostatectomy and/or radiation and no prior systemic therapy for prostate carcinoma recurrence maintained a reduced calcium diet and received calcitriol 0.5 μg/kg orally once each week until a maximum of a four-fold increase in the PSA.
Twenty-two patients received treatment for a median of 10 months (range, 2–25+ months). Treatment was well tolerated with no Grade ≥ 3 toxicity and no hypercalcemia or renal calculi. No patient had a PSA response (50% reduction confirmed 4 weeks later). Three patients (14%, 95% CI 0–28%) had confirmed reductions in the PSA ranging from 10% to 47%. Statistically significant increases in the PSA doubling time (PSADT) were seen in three additional patients and no patient had a shorter PSADT after starting treatment. For the entire study population, the median PSADT increased from 7.8 months to 10.3 months (P = 0.03 by Wilcoxon signed rank test).
Initial treatment for prostate carcinoma that is confined to the prostate gland is designed to permanently eradicate the disease. Depending on stage and grade at diagnosis, 15–80% of patients treated with surgery or radiation eventually suffer disease recurrence.1, 2 A rise in the prostate specific antigen (PSA) commonly precedes clinically detectable recurrence of prostate carcinoma and is accepted as evidence of prostate carcinoma recurrence.3, 4
No consensus has emerged regarding treatment of patients with a rising PSA after surgery or radiation. Selected patients may benefit from additional local therapy,5, 6 but many such patients do not achieve durable disease control with salvage local modalities. These patients are offered observation or androgen deprivation therapy.
The appropriate timing of androgen deprivation therapy in the management of prostate carcinoma remains uncertain. Studies that compared immediate hormonal therapy with therapy delayed until cancer-related symptoms developed in patients with locally advanced or metastatic prostate carcinoma have yielded conflicting results.7–9 No randomized studies have examined the utility of hormonal therapy in patients whose only evidence of disease is a rising PSA after definitive local therapy. Without treatment, most such patients remain free of clinically detectable prostate carcinoma for several years and in selected series as long as a median of 8 years.1 Lack of definitive evidence of a survival benefit coupled with the morbidity of androgen deprivation therapy limit the routine use of androgen deprivation in men with a rising PSA after surgery or radiation.10 Low-toxicity alternatives that slow or arrest the progression of recurrent prostate carcinoma are needed.
There is ample preclinical evidence supporting the evaluation of vitamin D receptor (VDR) ligands in prostate carcinoma. Both tissue culture systems11–16 and mouse models16–18 demonstrate the activity of VDR ligands in prostate carcinoma, particularly at supraphysiologic concentrations. Physiologic levels of calcitriol range from 0.05 to 0.16 nM. Significant growth inhibition has been found to require calcitriol concentrations of 1 nM (416.7 pg/mL) or higher in most studies.14, 15
Gross et al. treated seven patients with rising PSAs after radiation or prostatectomy with daily calcitriol.19 Six of seven patients appeared to have slowing in the rate of PSA rise with daily calcitriol therapy. Daily dosing is limited, however, by predictable development of hypercalcemia and hypercalcuria and is unlikely to produce significantly supraphysiologic blood calcitriol levels. Intermittent dosing permits substantial escalation of the calcitriol dose. Subcutaneous dosing every other day produced peak blood calcitriol levels of 0.7 nM.20 In a Phase I study that examined 4 weeks of weekly oral administration with a reduced calcium diet, peak blood calcitriol levels of 3.7–6.0 nM were reached with little toxicity.21 The dose of 0.5 μg/kg was identified for further investigation in this Phase II trial.
The study reported here examined weekly calcitriol at a dose of 0.5 μg/kg in patients with a rising PSA after radiation and/or surgery. The goals of the study were to evaluate the safety of long-term administration of weekly pulse calcitriol and to evaluate the impact of pulse calcitriol on prostate carcinoma progression as measured by the PSA. In subsets of patients, this study also sought to evaluate calcitriol pharmacokinetics at the onset of treatment and after several months of therapy and to examine the impact of treatment and of the reduced calcium diet on calcium homeostasis.
MATERIALS AND METHODS
Eligibility criteria included: histopathologically or cytologically proven adenocarcinoma of the prostate treated with either prostatectomy and/or definitive radiation; rising PSA after the postdefinitive therapy nadir on at least three measurements at least 2 weeks apart; PSA ≥ 0.4 ng/mL for prostatectomy patients and ≥ 1.0 ng/mL for radiation patients; Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3; serum creatinine ≤ 1.3 mg/dL; serum calcium ≤ 10.5 mg/dL; and serum phosphate ≤ 4.2 mg/dL.
Patients were excluded for prior systemic treatment for prostate carcinoma recurrence, history of hypercalcemia, renal calculi within 5 years, uncontrolled heart failure or significant heart disease including myocardial infarction in the last 3 months, and known cardiac ejection fraction < 30%. Prohibited concomitant medications included thiazide diuretics, digoxin, magnesium-containing antacids, bile resin binding drugs, and calcium supplements. The protocol was approved by the Institutional Review Boards of Oregon Health & Science University and Portland VA Medical Center. Written informed consent was obtained from all patients.
Patients were instructed to maintain a reduced calcium diet with the goal of limiting daily calcium intake to < 500 mg throughout the treatment period as previously described.21 Patients were also asked to drink 4–6 cups of water in addition to their usual fluid intake beginning 12 hours before each dose and continuing for 3 days.
Calcitriol (Rocaltrol®, 0.5 μg capsules; Roche Pharmaceuticals, Nutley, NJ) 0.5 μg/kg was given orally once a week. Each weekly dose was divided into 4 doses and taken orally during each hour of a 4-hour period. Calcitriol treatment was continued until a maximum of a four-fold rise in the PSA or earlier if patients developed any clinical evidence of disease progression. In some patients, treatment was discontinued before a full four-fold increase at patient request.
Baseline evaluation included a complete history and physical exam, complete blood count, serum creatinine, serum calcium, serum phosphate, total serum bilirubin, alanine aminotransferase (ALT), alkaline phosphatase, albumin, 24-hour urine creatinine clearance, and bone scan.
Complete blood count, serum chemistries, and PSA were checked monthly. In addition, serum calcium was checked weekly. If normal for 4 consecutive weeks, serum calcium was then monitored every other week for 4 weeks, and if normal, monthly thereafter. Twenty-four-hour urine creatinine clearance was repeated every 6 months.
All toxicities were graded according to National Cancer Institute (NCI) Common Toxicity Criteria.
Assessment of Endpoints
This study sought to examine the safety of long-term treatment with pulse calcitriol. The primary efficacy endpoint was PSA response defined as a 50% reduction in PSA confirmed by two measurements at least 4 weeks apart.22 Statistically significant increase in the PSA doubling time (PSADT) was a secondary efficacy endpoint. Detailed examinations of pulse calcitriol pharmacokinetics, of the impact of pulse calcitriol on calcium and phosphate metabolism, and of the impact of the reduced calcium diet on the toxicity of therapy were carried out in subsets of patients as outlined below.
The sample size calculation was based on the primary efficacy endpoint. A two-stage study design was used with the goal of rejecting the regimen if the response rate was < 10% and recommending the regimen for further study if the response rate was ≥ 30%. The minmax design, which allowed the smallest possible maximum sample size with α = 0.05 and β = 0.20, would reject the regimen if < 2 of 15 patients responded in the first stage. It would recommend the regimen for further study if ≥ 6 of 25 patients responded in the second stage.23 Accrual beyond 15 patients was permitted while the primary endpoint was being evaluated in the first 15 patients.
PSADT was calculated as LN(2)/regression coefficient of the PSA rise. The regression coefficient of the PSA rise and 95% confidence intervals were calculated using linear regression analysis with LN(PSA) as the dependent variable and time the independent variable using StatView 5.0 software (SAS Institute, Cary, NC). The pretreatment PSADT was calculated using all available PSA values that spanned one doubling of the PSA. Nonoverlapping 95% confidence intervals were required for statistical significance.
Pharmacokinetic assessment was planned in up to six patients at baseline and after approximately 3 months. Patients were admitted to the clinical research center inpatient unit for the first 24 hours and blood samples of plasma and serum obtained immediately prior to calcitriol administration and at 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, 15, and 24 hours following calcitriol administration. They then returned daily for blood draws on Days 3, 4, 5, 6, and 8. 1,25-dihydroxyvitamin D levels were measured by a radioreceptor assay with calf thymus 1,25-dihydroxyvitamin D receptor, using the method of Reinhardt, et al.24 The maximum calcitriol concentration (Cmax) and time of maximum calcitriol concentration (Tmax) was determined by visual inspection. The area under the curve (AUC) was calculated using the linear trapezoidal rule.25
Patients who participated in the pharmacokinetics substudy also had serum calcium and phosphate and urinary calcium and phosphate excretion monitored for an 8-day period beginning 24 hours before dosing.
Up to six participants who had no hypercalcemia while adhering to the reduced calcium diet were invited to participate in a substudy designed to examine the contribution of dietary restriction to the safety of the regimen. During the first week, patients were monitored while on the reduced calcium diet. Serum calcium and phosphate were measured just prior to treatment and then approximately 24, 48, and 72 hours later. Twenty-four-hour urine for calcium was collected the day prior to dose, day of the dose, and 1, 2, and 3 days after the dose. Patients filled out a dietary questionnaire designed to assess their dietary intake as previously described.21 For the next 4 weeks, patients resumed their normal dietary habits while maintaining the increased fluid intake requirements. For 1 week, patients had intensive monitoring as described above. In the subsequent 3 weeks, weekly calcium and phosphate were drawn on Day 3. Patients who completed this substudy without ≥ Grade 2 hypercalcemia were permitted to remain on a calcium-unrestricted diet for the remainder of their time on study.
Twenty-four men were recruited between February 1999 and July 2000. Two were ineligible (one due to prior hormonal therapy for recurrent prostate carcinoma and the other because his PSA was not rising). Results in the 22 eligible patients are reported here. Pretreatment patient characteristics are summarized in Table 1. Briefly, the median age was 69 and median ECOG performance status was 0. The median PSA was 5.8 ng/mL (range, 1.1–38.6 ng/mL). None of the patients had bone metastases. Prior therapy included prostatectomy in eight patients, external beam radiation in five patients, and both prostatectomy and external beam radiation in nine patients. Three of these patients had received neoadjuvant hormonal therapy in addition to treatment directed at the primary tumor.
Table 1. Characteristics of Patients Enrolled in Study
The study was initiated prior to the publication of the prognostic model from Pound et al.1 The eligibility criteria were therefore not designed to identify particularly high-risk patients. Four of the 16 patients who had a prostatectomy had a Gleason score > 7. Fourteen of 22 patients has a PSADT < 10 months. Fourteen of 22 patients had a PSA recurrence within 2 years of initial treatment.
One patient remains on therapy in the 25th month. The median followup for the entire study population is 24 months (range, 21–36 months).
Twenty-two patients received treatment for a median duration of 10 months (range, 2–25+ months). Twenty-one patients have discontinued treatment. Two patients withdrew due to toxicity: one due to exacerbation of preexisting atrial fibrillation (Grade 2) and the other due to Grade 1 creatinine elevation. Two patients withdrew due to the development of metastatic disease and two due to a four-fold increase in the PSA as specified in the protocol. The remaining 15 patients withdrew at their request or the recommendation of their physician due to a rising PSA that rose less than four-fold. In this group, the median PSA rise was 2.4-fold (range, 1.5–3.4).
No deaths occurred. No Grade 3 or higher toxicity was seen. All observed toxicities are reported in Table 2. Therapy was not withheld or delayed due to toxicity with the exception of the two patients outlined above. Notably, no hypercalcemia or renal calculi were seen. Of the five patients with Grade 1 creatinine elevations, one remains on study with creatinine measurements that oscillate between normal and minimally elevated, two returned to normal while continuing calcitriol therapy without dose reduction, one returned to normal after discontinuing therapy, and one had persistent Grade 1 creatinine elevation despite discontinuing treatment.
In the 15 patients for whom creatinine clearance measurements were available, no difference was detected between baseline and after 6 months. The mean creatinine clearance was 125 mL/min (95% CI, 107–143 mL/min; median, 113 mL/min) at baseline and 116 mL/min (95% CI, 102–131 mL/min; median, 118 mL/min) after 6 months of treatment (P = 0.23 by paired t test). Creatinine clearance measurements were available at baseline and after 12 months of treatment in nine patients. The mean creatinine clearance in these patients was 109 mL/min (95% CI, 100–118 mL/min; median, 108 mL/min) at baseline and 90 mL/min (95% CI, 78–103 mL/min; median, 86 mL/min) after 12 months of treatment (P = 0.02 by paired t test).
Six patients participated in an assessment of calcitriol pharmacokinetics at the initiation of therapy (Fig. 1). Five of these patients had a second set of samples collected approximately 3 months later (Fig. 2). Table 3 summarizes pharmacokinetic parameters at the beginning of treatment (n = 6) and approximately 3 months later (n = 5). There was no statistically significant difference in the Cmax, AUC(0-inf), Tmax, T1/2, although there was a trend toward earlier Tmax (P = 0.09) and shorter T1/2 (P = 0.10) after 3 months of therapy.
Table 3. Pharmacokinetic Parameters of Calcitriol Administered in the First Week of Therapy (n = 6) and Approximately 3 Months Later (n = 5)
CI: confidence interval; AUC: area under the curve.
Two-tailed, paired t test.
Cmax, pg/mL (95% CI)
Tmax, h (range)
AUC(0-inf), pg · h/mL (95% CI)
T1/2 h (95% CI)
Effects on Calcium Metabolism
Daily serum and 24-hour urine phosphate before dosing and for 7 consecutive days after dosing were collected in six patients at the initiation of therapy and in five of these six patients approximately 3 months later. There was no difference between the results obtained at the beginning and after 3 months of therapy (data not shown). No serum calcium measurements were out of the normal range (>10.5 mg/dL). Both the mean serum calcium and mean 24-hour urinary calcium peaked 2 days after treatment and returned to baseline within 48 hours. The mean serum calcium prior to treatment was 9.2 mg/dL (95% CI, 9.0–9.4 mg/dL) and was 9.8 mg/dL (95% CI, 9.6–10.0 mg/dL) 2 days after treatment. Similarly, the mean 24-hour urinary calcium excretion prior to treatment was 243 mg (95% CI, 166–320 mg) and was 339 mg (95% CI 303–379 mg) 2 days after treatment. Mean serum phosphate levels peaked 1 day after therapy and returned to baseline levels within 48–72 hours (data not shown), while remaining within the normal range. Twenty-four-hour urinary phosphate excretion remained within normal limits throughout the 7-day period and no clear change with time was observed (data not shown).
Five patients participated in the diet substudy. The estimated mean daily calcium intake on the restricted diet was 433 mg (range, 338–614 mg). On the unrestricted diet, it was 541 mg (range, 403–612 mg). All serum calcium measurements remained in the normal range despite the liberalized diet. The mean peak serum calcium concentration on the restricted diet was 9.5 mg/dL (range, 9.0–10.2 mg/dL) and was 10.0 (range, 9.3–10.3 mg/dL) on the unrestricted diet. The peak mean 24-hour urinary calcium excretion was 303 mg (range, 172–357 mg) on the restricted diet and 412 mg (range, 341–541 mg) on the unrestricted diet. The changes observed do not reach statistical significance, but the sample size is too limited to exclude a modest increase in serum calcium and urinary calcium excretion when dietary calcium intake is liberalized. As one might expect in an elderly population, even a liberalized diet was relatively low in calcium.
No patients met the primary efficacy endpoint of a confirmed 50% reduction in the PSA. Lesser reductions in the PSA (confirmed reductions of 47%, 28%, 10%) were seen in three patients. In these three patients, PSA remained below baseline for 4.5, 19.3, and 22.6+ months, respectively. In three additional patients, PSADT increased significantly (559%, 353%, and 143% of pretreatment). The remaining 16 patients had no statistically detectable change in the PSADT.
The median PSADT for the entire study population increased from 7.8 months to 10.3 months (P = 0.03 by Wilcoxon signed rank test).
Weekly oral dosing safely yields peak plasma concentrations > 1 nM. To our knowledge, this is the first prostate carcinoma clinical trial that examined single-agent calcitriol given by a method that produces peak plasma calcitriol concentrations higher than the minimum necessary for significant growth inhibition in vitro. The primary endpoint of this study, confirmed PSA reduction of ≥ 50%, was not achieved. This endpoint was chosen because calcitriol has established pro-apoptotic, antiproliferative, and antiangiogenic activity in preclinical models at sufficiently high concentrations. Nevertheless, this endpoint appears to have been too ambitious for this agent. The secondary analyses of PSA changes showed PSA reductions short of the 50% mark in three patients, statistically significant lengthening of the PSA doubling time in an additional three patients, and an increase in the doubling time in the entire study population. These findings suggest that high-dose weekly calcitriol may have some antineoplastic activity in human prostate carcinoma.
These secondary PSA endpoints have not been validated, however, and should be viewed solely as hypothesis generating. PSA doubling time has been tightly linked with the likelihood of metastatic progression in patients with a PSA recurrence after both surgery and radiation therapy.1, 26–29 Whether treatments that lengthen PSA doubling time in this setting would delay development of metastases or extended survival is not known. Nonetheless, in a disease associated with a median time to metastases of 8 years and median survival of 13 years,1 treatments that can slow tumor progression with minimal toxicity may deliver important clinical benefits. Further studies of weekly high-dose calcitriol that are designed to determine whether weekly oral calcitriol can induce clinically important delay in cancer progression are warranted. Such studies should be randomized, placebo controlled, and target a patient population at relatively high risk of metastatic progression.
Initial Phase I evaluation of this regimen was limited to four weeks of calcitriol administration; therefore, this study provides new information about the safety of long-term calcitriol therapy. Treatment was well tolerated with no Grade 3 toxicity. No hypercalcemia or renal calculi were detected. Grade 1 creatinine elevations were observed in several patients. The majority of these resolved either during continued treatment or after treatment discontinuation. Renal function, measured by 24-hour creatinine clearance, was unchanged in the study population after 6 months of treatment. In a smaller sample of patients who received 12 months of therapy, a modest reduction in the creatinine clearance was found. No followup creatinine clearance measurements after discontinuation of therapy are available for these patients. Future studies of long-term weekly oral calcitriol should include periodic monitoring of renal function.
In a small subset of patients, we did not find large changes in serum calcium concentration or 24 hour urinary calcium excretion and did not observe any adverse effect of a calcium-unrestricted diet. Future studies should examine this regimen without a calcium-restricted diet (perhaps still limiting calcium supplementation) and monitor potential calcium-associated toxicity.
It was possible that prolonged administration of high doses of calcitriol would induce calcitriol metabolism and reduce calcitriol exposure over time. The activity of 24 hydroxylase in the murine gastrointestinal mucosa is induced by calcitriol administration.30, 31 Calcitriol pharmacokinetics, monitored in a subset of patients at the onset of treatment and after 3 months, do not show a significant reduction in the Cmax or AUC of calcitriol despite prolonged therapy.
The commercially available formulation of calcitriol used in this study required patients to consume a large number of capsules each week. Patients reported only modest inconvenience associated with consuming 1 pill/kg/week, although this cohort of patients was highly motivated. It is not known if compliance with this regimen would remain high if it were utilized outside of a tightly controlled clinical trial setting. A high-dose formulation of calcitriol, currently in development, may enhance compliance with this regimen.
In summary, the long-term administration of weekly calcitriol has been found to be safe. Future studies of long-term treatment with this agent should evaluate treatment without dietary calcium restriction and should include monitoring of renal function. Based on the primary efficacy endpoint, weekly high-dose calcitriol alone has no activity in hormone-naïve prostate carcinoma. The changes in PSA and PSADT that were observed suggest that weekly high-dose calcitriol may slow the rate of disease progression. Randomized studies that measure time to clinical progression are needed to definitively examine the impact of this regimen on the natural history of hormone-naïve prostate carcinoma.
The authors thank Gilbert Lam for his assistance with analysis of pharmacokinetic data and Scott Cruikshank for statistical analysis assistance.