HDPC = high dose pulsed calcitriol (as .5mcg calcitriol/kg of body weight the day before docetaxel/taxotere)

Calcitriol = 1,25-dihydroxycholecalciferol (1,25 DHCC; 1,25 dihydroxyvitamin D3, Rocaltrol, Calcitriol)

Docetaxel = taxotere

mcg = micrograms.

kg = kilograms (of body weight).

Introduction

Calcitriol has many interesting properties.  Of relevance here is its role as a chemotherapy sensitizing agent. Calcitriol by itself does not provide an effective anti-HRPC disease treatment.  See also the original paper by Bill Aishman on calcitriol.

A list from pre-clinical studies includes:

• induces cell cycle arrest (G0/G1) and differentiation. Note: G0 is the resting phase and G1 is the portion of the cell cycle when RNA and protein synthesis production starts increasing.

• inhibits proliferation of multiple cancer cell lines.

• downregulates genes that inhibit apoptosis.

• decreases invasiveness and inhibits angiogenesis.

• shows synergy with several cytotoxic agents.

D. Trump, MD wrote in the October 2007 Hem/Onc Today: "Our own research group has noted in murine (mouse) and canine (dog) models that calcitriol in high dose potentiates the in vivo antitumor effect of cisplatin, paclitaxel, gemcitabine (Gemzar, Eli Lilly) and mitoxantrone. Accrual of patients is ongoing." The potentiation of HDPC and Taxol (paclitaxel) is weak as documented in taxol and HDPC

With Taxotere (docetaxel), the potentiation appears to be well established, there having been several clinical trials studying this combination. Lastly, combining HDPC and mitoxantrone has some trial data to support using this combination -- see mitoxantrone.

Trump also wrote, in the same article, that "Finally, many investigators have shown that calcitriol potentiates the antitumor activity, in vivo and in vitro, of a number of cytotoxic agents:

• taxanes (especially taxotere)

• anthracyclines (doxorubicin, mitoxantrone) - the general class is "antitumor antibiotics"

• alkylating agents (cisplatin, cytoxan)

• antimetabolites (gemzar)"

Calculating the dose of HDPC as Originally Implemented by T. Beer et al (2)

Dose of Calcitriol(1, 2): .5 mcg/kg of body weight, taken the day before taxotere. For example: Patient weight 73kg. 73kg x .5mcg = 36.5mcg or 36.5mcg/.5mcg/pill = 73 pills.  An easy way to figure this out is that the number of .5mcg pills taken = Patients weight in kilograms. 80 kg patient would take 80 .5mcg pills.

Another example: 200 lbs. / 2.207 lb/kg  = 90.62 kg, .5 x 90.62 = 45.31 mcg, but each pill is .5 mcg so it takes 45.31x2 = 90.6.

Beer et al (2) further gave more details on how best to ingest all of these pills.

Calcitriol is also available for IV as Calcijex Injection: 1 mcg/ml, 2 mcg/ml RX. One patient reports this: Started on a low dose of the Calcitriol (IV) for the initial treatment.  He used 4mcg of Calcitriol in the drip – a small bag, not one of the larger size. Plans to increase the dose of Calcitriol.

(Note:The safety of using the IV form has not been evaluated.) Trump wrote in the Oct 2007 Hem/Onc Today the following about the IV form: "While considerable work remains, these data suggest that calcitriol in high doses may be a useful adjunct to standard cancer chemotherapy. A pressing issue that requires delineation is the appropriate dose of high-dose calcitriol. It is clear that high-dose intermittent therapy is safe and nontoxic. We have given up to 100 mcg per week by IV without toxicity, and we are conducting a phase-2 trial in prostate cancer with 77 mcg IV weekly, with no appreciable toxicity. Therefore, determination of the optimal or maximally tolerated dose of calcitriol is a critical step in evaluating this agent as a drug for use in cancer therapy."

Clinical Trials of HDPC/Taxotere. Reference #2(TM Beer et al) all patients were chemo-naive. NM Tiffany et al, conducted their trial with every 3 week taxotere (hence HDPC is once every 3 weeks.) - 13 of 24 previously had taxotere.  Petrioli R et al studied weekly dosing, but with patients who had failed previous taxotere chemotherapy.

Table 1. Docetaxel in combination with high dose calcitriol and with or without Estramustine Phosphate (Emcyt). (updated 21 August 2009.)

(a) 60mcg calcitriol is a much higher dose than the usual .5mcg/kg of body weight previously used for weekly dosing. 

(b) Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Four patients had thromboembolic complications.

(c) 18 pts previously treated with weekly epirubicin 30mg/m2 and docetaxel 30mg/m2; 6 with weekly docetaxel 30mg/m2 and two with 3-weekly docetaxel (75mg/m2).  Pts continued to receive bisphosphonates, which were started after failure of 1st-line chemo in all patients with bone mets (24 pts). The median(range) interval between the end of 1st-line chemo and the start of high dose calcitriol and docetaxel was 13 (2-72) weeks. The median duration of the PSA response was 3.8 (2.2-5.4) months.

(d) Toxicity was characterized as very mild. Grade 3 neutropenia in 2 patients and hypercalcaemia (probably related to calcitriol) in only 1. All of the patients discontinued first-line treatment with docetaxel because of progressive disease, which occurred during and within 60 days of docetaxel therapy.

 (1) Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM, High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study, J Urol. 2005 Sep;174(3):888-92. This was published earlier in abstract form at ASCO 2004, Abstract 4678.

(2) Tomasz M. Beer, Kristine M. Eilers, Mark Garzotto, Merrill J. Egorin, Bruce A. Lowe, W. David Henner, Weekly High-Dose Calcitriol and Docetaxel in Metastatic Androgen-Independent Prostate Cancer; Journal of Clinical Oncology, Vol 21, Issue 1 (January), 2003: 123-128.

(3) Petrioli R, Pascucci A, Francini E, Marsili S, Sciandivasci A, De Rubertis G, Barbanti G,
Manganelli A, Salvestrini F, Francini G. Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel, BJU Int. 2007 Oct;100(4):775-9. Epub 2007 May 29. The authors noted that with "no standard salvage therapy available we hypothesised that high-dose calcitriol might restore sensitivity to chemotherapy."
 

Some Observations Regarding Sequential Use of Taxotere (≥ 2nd line chemo). See paper #3 (Petrioli R et al.)

In selecting a 2nd chemotherapy, distinguish between patients who stop their firstline treatment with taxotere while still responding to the drug because they have completed a planned course of therapy or desire a break due to adverse effects. (they might also be eligible for intermittent chemo where taxotere is used, PSA is lowered, stop taxotere, PSA starts rising, re-start taxotere.

Thus there is an important distinction between patients who have truly docetaxel-resistant disease and those who have been exposed to docetaxel and now have progression, but might still have docetaxel-sensitive disease. In this group of patients a repeated treatment with docetaxel might be appropriate if progression occurs after a reasonably long interval (6-12 mos or more). 

Petrioli (3) et al, say that "therefore the characteristics of the patients seem to support an effective role of high-dose calcitriol in restoring sensitivity to the drug."

Note, however, that seven of eight responses were in patients who had shown an initial response to previous docetaxel as first-line treatment. This finding suggests that the apparent restoration of sensitivity to the drug by using high-dose calcitriol might develop almost exclusively in those patients who previously had a response to first-line treatment with docetaxel-based chemotherapy.