Calcitriol
as an Antitumor Agent and
Enhancer of Chemotherapy Agents
A Patient’s Perspective
July 2003
SUMMARY.....following Dr. Beer’s recently
published studies of high-dose calcitriol combined with Taxotere, there is
considerable interest in the subject of calcitriol as a treatment for
prostate cancer and thus, another possible addition to treatments in our
arsenal to combat this chimera that invades our bodies and lives.
Serious studies of the role of calcitriol in the treatments
for cancer are reported as early as 1999 concluding that it has considerable
anti-tumor effects and recent trials reflect that it enhances the anti-tumor
effects of taxanes and platinum analogs. But, the dosage, scheduling, and
small patient population clearly reflect that more studies are needed before
the agent is a confirmed addition to our arsenal of tools to combat prostate
cancer.
Below I have summarized the history and trial results
reflecting the possibility that this is a new agent to affect our disease
and perhaps complement our chemotherapy protocols.
ACRONYMS and DEFINITIONS...
AUC = area under the curve --area under plasma drug
concentrations vs. time curve; a measure of drug exposure---i.e., doses of
Carboplatin are expressed as an AUC designation (vs. just a mg/m2) for
explicit accuracy in dosing---computed as: dose (in mg) = target AUC x (creatinine
clearance + 25).(1)
AIPC =
androgen-independent prostate cancer.
bid --
twice/day
DVT -- deep
vein thrombosis = blood clots.
tid -- three
times/day
Q21 or q21 --
every 21 days
po -- orally,
by mouth
PCa --
prostate cancer
TX --
treatment
RR --
response rate = % of patients that experienced >50% reduction in PSA--
HDCal =
high-dose calcitriol. Beer uses HDPA calcitriol where hdpa = high dose
pulsed administration.
hypercalcemia
= an abnormally high concentration of calcium compounds in the circulating
blood.
MDR --
median duration of response = months after TX start to disease
progression.
MDS --
median duration of survival = months after TX start to death, OR
LAST PATIENT CONTACT.
mg/m2
--milligrams of agent per meter squared of skin surface; easily calculated
by your doctor based on height and weight.
subcutaneous
= hypodermic; beneath the skin.
TX
---treatment.
DISCUSSION
Several medical journal studies have explored the use
of calcitriol as a single agent, chemotherapy agents as single agents, and
calcitriol in combination with chemotherapy and other agents for the
treatment of prostate cancer.
To develop the HDCal + Taxotere protocol, Beer (and
others) logically and methodically studied: a) single agent calcitriol, b)
single agent weekly Taxotere, c) the activity/feasibility of calcitriol with
other agents and, c) a combination of calcitriol and Taxotere.
a) Single agent calcitriol
As a single agent, Lowe BA et al. established that
weekly HDCal @ 0.5 mcg/kg po was safe but PSA declined in only 3/22 patients
(47%, 28%, 10%) and significant PSA slope increased in 3/22 patients (559%,
353%, 143%).(2)
Continuing to explore the activity of single agent
calcitriol, Beer TM, et al. reported a trial of 22 patients with
rising PSAs following RP or RT as ‘cures’; objective: define long-term
toxicity of weekly HDCal until a maximum of a four-fold increase in PSA was
experienced; no hypercalcemia or renal calculi (restrictions); RR = 0%, but
3/22 patients had reductions of 10-47%; and, median PSADT increased from 7.8
months to 10.3; conclusion: long-term HDCal is safe, but >50% reduction in
PSA was not achieved in any patient in this cohort of failed ‘cures’.(3)
b) Single agent Taxotere
In addition to several similar trials, Berry W., et al.
reported a trial of 60 AIPC men (but, 21% had received prior RT and 25% had
received prior chemotherapy) with progressive metastatic PCa in a protocol
of weekly (6/8) single agent Taxotere @ 36 mg/m2 with RR of 41% (27%
had > 80% PSA reduction), MDR 5.1 months (0.9-18.2), MDS 9.4 months
(1.6-18.2).(4)
To establish his own basis for the responses and toxicities
for single agent Taxotere, an early Beer trial of 25
patients in a protocol of weekly (6/8) Taxotere @ 36 mg/m2 as a single agent
TX resulted in RR of 46% (many such trials report ~ 45-50% RR) and a
palliative response of 48% with modest toxicity.(5)
c) Activity/feasibility of calcitriol with other agents
Exploring alternative possibilities for calcitriol in TXing
PCa, escalating doses of calcitriol combined with zoledronic acid (Zometa)
in 29 patients found no hypercalcemia or hypercalciuria (excretion of above
normal amounts of calcium in the urine); no partial or complete soft-tissue
tumor responses; no improvement in bone scans; no significant antitumor
effects, but a reduction in bone resorption markers; and, 41% had a >50%
decline in PSA slope.(6)
Calcitriol has considerable antitumor effects in a variety
of tumor models; it induces apoptosis (death), cell cycle arrest, and
enhances antitumor activity of Cisplatin and Carboplatin; enhancement is
sequence dependent as enhanced activity is only observed when it is given 24
hours before the platinum analog; there is no indication that it enhances
the myelosuppressive (reduced blood markers) effects of Carboplatin.(7)
Calcitriol potentiates the inhibitory effects and efficacy of paclitaxel
(Taxol) and, the hypercalcemic effects of calcitriol are reduced by
Taxol treatment = synergy between the antitumor agents.(8)
Pretreatment with calcitriol (subcutaneous) enhances the antitumor
effects of taxanes and platinum analogs; but the sequencing is important:
AUC of Taxol was not different with or without calcitriol; AUC of
Carboplatin was higher in every patient if calcitriol was given before
Carboplatin vs. after Carboplatin; but, myelosuppression was
considerably less when calcitriol was administered after Carboplatin
= consistent with the difference in AUC (we are between a rock and a
hard place--choosing between greater cell kill vs. blood marker
deterioration?); the potentiation of Carboplatin by calcitriol may be
related to reduced Carboplatin clearance.(9)
Harshberger reported that in vitro studies of
HDCal + Taxol establish that the combination interacts synergistically and
results in substantially greater growth inhibition than either agent alone;
his work demonstrated that 24 hours after treatment with calcitriol,
p21 expression was reduced and Taxol cytotoxicity was enhanced without an
increase in apoptosis, whereas at 48 hours, calcitriol accelerated Taxol
apoptosis.(10 & 16) Thus, pre-treatment with calcitriol is schedule
dependent for maximum effect.
And, in a HDCal + dexamethasone trial it was found
that the combination of the agents was safe with clear anti-tumor
effects; RR 21% and reduction of PSA velocity 79%.(11)
d) Combining calcitriol and Taxotere
In an early (2001) study of 18 patients Beer’s
objective was to determine whether combining the above two agents (HDCal and
Taxotere) improves the therapeutic index of Taxotere = the addition of HDCal
may enhance the activity of weekly Taxotere.(12) Then, in a pilot
trial of 5 patients Beer established that HDCal @ 0.5 mg/kg produces
plasma calcitriol 25-fold higher than the physiologic (normal) range and
when combined with weekly Taxotere @ 36 mg/m2 the resultant RR was
100%.(13)
The report that generated the most attention to this
combination of HDCal + Taxotere was the Beer report in ASCO
2002 wherein the stated objective was to improve on the 38-46% RR of weekly
single agent Taxotere; he attained his objective with a cohort of 36
patients and a RR of 77%--- conclusion: HDCal enhances
the activity of Taxotere without a significant increase in toxicity.(14)
Meanwhile, continuing the discovery process of all aspects
of this HDCal + Taxotere protocol, Beer TM, et al.
investigated the palliative effect of weekly HDCal + Taxotere in a trial of
37 patients; the TX resulted in 48% palliative response (note: this is the
same palliative response as reported in ref 4, which was single agent
Taxotere); MDR 7.1 months (2-23.2); conclusion: HDCal + Taxotere has
significant palliative activity.(15)
Subsequently, with combined weekly HDCal + Taxotere,
Beer TM, et al. achieved a higher response in 37 men with metastatic
AIPC; RR 81% (59% with > 75% PSA reduction); MDR 11.4 months (8.7-14); MDS
19.5 months (15.3-incalculable) (16)----this trial confirms
that weekly (6/8) HDCal + Taxotere substantially exceeds the response rate
of weekly single agent Taxotere (RR 45-50%), and equals the Petrylak/Saverese
Q21 Taxotere + Emcyt protocols (RR 75%; MDS
22.8 months) (17), and without the added toxicity (and nastiness,
IMO) of Emcyt.
The current protocols require 60-80 pills/day to achieve the
dose level required for HDCal. An effort is underway to reduce this
pill-taking dosage and limited bioavailability/absorption of 0.5 mcg/kg to
one pill in the form of a new high-dose oral formulation of calcitriol,
called DN-101(now called ASENTARtm and being developed by Novacea;) 27 patients are reported in a dose-escalation trial to
determine MTD (maximum tolerated dose); single dose MTD has not been reached
at 90 mcg; MTD for repeat weekly dosing is 45 mcg; conclusion:
concentrations achieved with DN-101 appear higher than those achieved with
other oral calcitriol formulations and are sufficient for anti-neoplastic
(anti-growth) activity in pre-clinical models.(18) A trial is
recruiting for DN-101; requirements = DX of PCa with bone mets, 3 rising
PSAs or new metastatic lesion, adequate liver/kidney function, ongoing HB.(19).
The current clinical trial is ASCENT-2 - see
www.ascent-2.com and data from earlier
trials is at
http://www.novacea.com/230.asp.
Conclusions: I believe that Dr. Beer
has significantly contributed to the protocols for TXing PCa and he has
methodically and competently studied/reported results re single agent weekly
Taxotere and single agent HDCal, followed by combining weekly Taxotere +
HDCal--- and he has certainly proved his stated objective of enhancing the
efficacy of weekly Taxotere.
While the reports in general look very positive that weekly HDCal +
chemotherapy are effective, I suggest that the patient cohorts reported
are small, the trial participants were all chemo-naive, and the patient
populations included no failed ‘cure’ treatments (RP/RT).
Therefore, if you are chemo-naive with high-risk progressing disease,
perhaps the HDCal + Taxotere TX is an excellent choice since the risk of a
‘trial’ and the possibility of no response is positively modified because a
component of the TX is weekly Taxotere with a RR of ~50% as a stand-alone
protocol.
Otherwise if you are pre-TXd with chemo (especially if you have exhausted
the taxanes), perhaps the TX will be less than successful and another choice
in sequencing chemo TXs would be more appropriate to prevent a run-away
progression while on the TX?
I tried 5 TXs of the weekly HDCal + Taxotere off-trial and my PSA
increased from 29.2 to 47.8, but I was heavily-TXd with 2 years of chemo
prior to HDCal + Taxotere. After 3 years of exhausting all iterations of
hormonal ablation and SR 89/RT (for pain), I completed 46 TXs of weekly
single agent Taxotere, 6 TXs of Q21 Novantrone, and one month of daily
Cytoxan po before trying a return to Taxotere + HDCal. Obviously it did not
work for me. Thus, perhaps the weekly HDCal + Taxotere protocol is best
suited to patients who have exhausted hormonal ablation and are chemo-naive?
Caution: I suggest that in interpreting trials we must always remember
that "Extrapolating phase II data from a small single institution trial to
imply a survival benefit is misleading."(20)
Bill Aishman
NOTE: I am not a doctor and can not give medical advice. I am a
prostate cancer patient with advanced disease and I performed this layman’s
analysis for my own decision-making purposes. In conjunction with a medical
team, every cancer patient must make their own decisions regarding treatment
options. I make no claim that this analysis is definitive or complete.
References
(1) Calvert AH, et al.;
Carboplatin Dosage: Prospective Evaluation of a Simple Formula Based on
Renal Function; J Clin Oncol, Vol. 7, No. 11 (November), 1989:pp 1748-1756.
(2) Lowe BA, et al.; Long term
administration of high dose weekly calcitriol in patients with a
rising PSA after definitive treatment for prostate cancer: a phase II study;
ASCO 2002 # 2446.
(3) Beer TM, et al.; High-dose
weekly calcitriol in patients with a rising PSA after prostatectomy or
radiation for prostate carcinoma; Cancer 2003 Mar 1;97(5):1217-1224.
(4) Berry W., et al.; Phase II
trial of single-agent weekly docetaxel in hormone-refractory, symptomatic,
metastatic carcinoma of the prostate; Semin Oncol, 2001 Aug;28(4 Suppl
15):8-15.
(5) Beer TM, et al.; Phase II
study of weekly docetaxel in symptomatic androgen-independent prostate
cancer; Ann Oncol 2001 Sep;12(9):1273-9.
(6) Solit DB, et al.; Phase 1
study of high dose calcitriol and zoledronic acid in patients with prostate
cancer; ASCO 2002 # 777.
(7) Johnson C, et al.; The Effect
of 1,25 Dihydroxyvitamin D (calcitriol) on Carboplatin-Mediated Antitumor
Activity: Preclinical and Clinical Studies; ASCO 1999; Category: Clinical
Pharmacology.
(8) Trump D, et al.; Preclinical
and Phase 1 Studies of the Combination of Calcitriol (1,25 OH3 Vitamin D3 ) and Paclitaxel: Synergistic Antitumor Activity and
Reduced Toxicity; ASCO 1999; Category: Clinical Pharmacology.
(9) Johnson C, et al.; Effects of
High dose Calcitriol on the Pharmacokinetics of Paclitaxel or Carboplatin:
Results of Two Phase 1 Studies; ASCO 2000 # 820.
(10) Harshberger PA, et al.;
Calcitriol enhances paclitaxel antitumor activity in vitro and in vivo and
accelerates paclitaxel-induced apoptosis; Clin Cancer Res 2001
Apr;7(4):1043-51.
(11) Trump D, et al..; High dose
calcitriol + dexamethasone in Androgen Independent Prostate Cancer; ASCO
2000 # 1327.
(12) Beer TM et al.; Treatment of
Androgen-Independent Prostate Cancer with Weekly High-Dose Calcitriol and
Docetaxel; ASCO 2001 #2369.
(13) Beer TM, et al.; Weekly
high-dose calcitriol and docetaxel in advanced prostate cancer; Semin Oncol
2001 Aug;28(4 Suppl 15):49-55.
(14) Beer TM, et al.;
Androgen-independent prostate cancer treatment with weekly high-dose
calcitriol and docetaxel; ASCO 2002 # 707.
(15) Eilers KM/Beer TM, et al.;
Palliative activity of weekly high-dose calcitriol and docteaxel in
androgen-independent prostate cancer; ASCO 2003 # 1657.
(16) Beer TM, et al.; Weekly
high-dose calcitriol and docetaxel in metastatic androgen-independent
prostate cancer; J Clin Oncol 2003 Jan 1;21(1):123-8
(17) Petrylak DP, et al.;
Docetaxel (Taxotere) in HRPC; Semin Oncol 2000 Apr;27(2 Suppl 19):24-9.
(18) Beer TM, et al.; Phase 1
study and pharmacokinetic (PK) ecaluation of DN-101, a new formulation of
calcitriol; ASCO 2003 # 924.
(19)
www.centerwatch.com/patient/studies/STU37712.html
(20) Scher HI and Kelly WK;
Editorial: States and State Transitions Are All That Really Matter; J Urol,
Vol. 168, 2451-2453, December 2002.
Updated 9/29/06 by H. Hansen
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