Leukine, Leukine/Retinoids, Leukine/Thalidomide and Leukine/High Dose Ketoconazole - Extending the Off Period During Intermittent Chemotherapy

These combinations may also be useful in delaying the start of chemotherapy.

In its simplest form, intermittent chemotherapy means being on treatment for a certain number of weeks or months, having a good response as indicated by at least a 50% decrease in PSA and/or a PSA < 4ng/ml and then stopping any treatment while the body recovers from the treatment. TM Beer et al (1) published the results of a study on intermittent chemotherapy in hrpca patients which indicated improvement of fatigue and other chronic toxicities of chemotherapy.

However, for the majority of patients, some form of active treatment is probably necessary when stopping chemotherapy in order to provide an extended time off treatment. Extended time off might be accomplished by having a significant decline in PSA as in the Beer study or by smaller declines or just stabilization of PSA. Even a reduction of PSADT might prove beneficial.

The focus of this paper is on the use of GM-CSF(Leukine, or granulocyte-macrophage colony stimulating factor); retinoids (forms of vitamin A); combinations of Leukine and retinoids; and Leukine in combination with thalidomide for providing an extended off chemotherapy duration.

Introduction

Hormone Refractory Prostate Cancer patients face a real dilemma in attempting to extend their survival. On the one hand, they desire a reasonable level of quality of life (QOL) and on the other hand they want to survive as long as possible which may require the use of cytotoxic chemotherapies which may impact/lessen quality of life.

Second line hormonal therapy followed by sequential chemotherapies (e.g., taxotere/prednisone(or emcyt) to taxol/emcyt to mitoxantrone/prednisone to taxotere/carboplatin to taxotere/high dose calcitriol, etc.) might offer hrpca patients a chance to extend survival. The impact of sequential chemotherapies on quality of life is difficult to quantify as some patients tolerate the treatments very well, while others are greatly impacted by side effects such as ocular toxicity, peripheral neuropathy, fatigue and others. These may or may not resolve once chemotherapy has stopped. Intermittent chemotherapy in conjunction with sequential therapies may combine the best of both worlds – quality of life and extended survival.

There are at least 3 ways of maintaining disease control during the off-phase of chemotherapy. The 1st is that used in TM Beer et al’s study (1), i.e., no treatment (27% of his phase II study patients met the criteria for intermittent chemotherapy) which is an ideal situation. A second option is to use/re-use secondary hormonal treatments in the off-chemotherapy phase (e.g., ketoconazole, nilutamide, estrogen patches or DES), with possible low response rates and duration of response. The third option is to expose the prostate cancer cells to a totally new, non-chemotherapy agent such as Leukine. Retinoids such as all-trans retinoic acid or 13-cis retinoic acid may also play a role here as a way of increasing the effectiveness of GM-CSF (2), although as single agents, their activity for hrpca is limited. Conceptually, if the retinoids induce differentiation, then the GM-CSF might be enhanced in effectiveness against the prostate cancer cells(2). Recently, thalidomide in combination with leukine has entered the picture for this application(18).

Four drugs will be discussed here. They are:

For immune system modulation:
Leukine (GM-CSF, Sargramostim)

For induction of differentiation:
Vesanoid (tretinoin -- all-trans retinoic acid or "ATRA".)
Accutane (13-cis retinoic acid.)
(Not discussed here is calcitriol, which is said to have differentiation properties also).

For antiangiogenesis:
Thalidomide (Thalomid^®)

First a review of the clinical trials and other papers on Leukine (GM-CSF) is presented followed by a discussion on clinical trials with Retinoids and lastly the combinations of leukine and thalidomide or high dose ketoconazole/hydrocortisone.
 

GM-CSF at an Anti-PCa Agent

Overview.

GM-CSF( Sargramostim, Leukine) as a monotherapy has had several clinical trials and leukine clearly does have activity against hrpca.(3, 4, 5, 6, 7, 8) The dosing schedule in these papers has generally been 250 mcg/m2 at either 14 days continuously followed by 14 days off or 14 days continuously followed by a Mon-Wed-Fri schedule for 14 days of a 28 day cycle with the more continuous schedule providing better PSA control. While the attempt to limit toxicity by reducing the dosing schedule has merit, the lack of consistent PSA control argues for continuous daily dosing. B. K. Dieckgraefe, et al (9) found that continuous tx with leukine (8 weeks straight) had no more side effects than intermittent treatment. Additionally, C. I. Rivas et al (3) discuss leukine receptors and PCa and concluded that "These findings imply that both hyperplastic and neoplastic prostatic tissues may be responsive to GM-CSF."

Clinical Trials.

E J Small et al (5) studied Hrpca patients using 250mcg/m2(about 500mcg) leukine. Their cohort I had 14 days on leukine and 14 days off (23 men). About 50% of the men in cohort I experienced declines in PSA while on tx and rising PSA when tx was stopped in a sawtooth PSA pattern. Also 25% had a > 50% decline in PSA. Median response duration was 3.5 months with some men having responses longer than 9 months. Cohort II(13 men) had 14 days on leukine plus 3 days/week for the next 2 weeks. In cohort II, 12 of 13 had a median PSA decline of 32% with one patient having a >99% decline and an improved bone scan. The median survival of all patients was 15.8 months. Toxicity was stated to be minimal.

R. Dreicer et al (7) published a study using 250mcg of leukine on a M-W-F dosing schedule for 4 weeks and then repeated the treatment. There were 7 hormonally naïve and 9 androgen independent patients. Three of the 9 androgen independent patients had PSA responses "below baseline" and received all 6 months of tx. This suggests PSA stabilization in these patients. None of the 4 patients with measurable disease(1 – BS positive only, 3 – BS and CT scan positive) responded to leukine therapy. The lack of response is not surprising given the short time frame of the trial (6 months).

Rini et al (8) treated 30 patients with rising PSA post primary therapy(RP or RT.) The dose of leukine used was 250mcg/m2, 14 days of injections, followed by 14 days of no injections and then the cycle was repeated. Three of 29 patients (10%) had A PSA response (50% decrease). Twenty-six (90%) patients saw their PSA doubling time increase from 8.4 months to 15 months(the other 3 patients had PSA declines.)

On the basis of the above studies, it seems reasonable to use leukine as a therapy during the off period from chemotherapy. The lengthening of the PSA doubling time or achieving some disease stabilization, may translate into a longer off period than would otherwise be achievable. The question also arises as to whether or not there is a dosing schedule for the leukine that will improve on the intermittent leukine results noted above – say by daily injections. Daily dosing as used in (9), for Crohn’s disease, indicates that no additional toxicity accrues when using daily leukine injections for at least 8 weeks in a row. With the objective of having at least 6 months off chemotherapy, daily injections of leukine may be warranted.
 

Retinoids as Treatments for HRPCa

There are two FDA approved retinoid drugs available – Vesanoid(tretinoin -- all-trans retinoic acid or "ATRA") and Accutane(13-cis retinoic acid.) Both have seen some clinical trial testing as summarized below. Additionally, but not discussed here, there are retinoid receptors on both normal and malignant prostates (Y. Lotan et al (17).)

WK Kelly et al (10). They studied fourteen Hrpca patients were treated with ATRA (50 mg/m2 p.o. every 8 h daily). No PSA or objective disease responses were seen. However, they note there was a "potential differentiation effect."

S Culine et al (11). This paper used an intermittent dosing schedule of a single oral dose of 45 mg./m.2 ATRA daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. PSA RR was 15% (4 of 26 patients) and none of the 11 measurable disease patients showed an objective response.

DL Trump et al (12). 17 patients with HRPC received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. No PSA responses or objective disease responses. They say, "Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment."

M Galsky et al (13), in their review paper on the development of differentiation agents, is a good review paper that covers all the above and more. The role of retinoids as differentiation agents may be a key factor in their application to Hrpca. Galsky et al also say that perhaps longer exposure time to retinoids is required for them to be effective and hence patients with a lower disease burden (slowly advancing disease) would be better subjects.

Two studies of accutane (13-cis retinoic acid) and advanced PCa, but not Hrpca men, are available. Shalev et al (14) reported on 11 patients with rising PSAs post radical prostatectomy. The dose of accutane used was 1mg/kg/day for 12 months. Three of the 11 had a PSA reduction for 2-3 months and one had PSA stabilization for 3 months after an initial sharp PSA rise. They included a discussion of differentiation. Ferrari et al (15) in a study of 37 hormone naïve patients, could not determine if the HT plus accutane was superior to HT alone, but the addition of accutane to standard hormone therapy did not impair PSA decline or add significant toxicity. Ferrari et al also discuss differentiation effects.
 

Leukine and Retinoids

Clinical trials in hrpca patients of the combination of leukine and retinoids have yet to be done. H Nakajima et al (16) touch on the potential synergistic action of ATRA and leukine via ATRA's ability to stimulate production of gm-csf. This is an in vitro study.

Some clinical experience with leukine and retinoids is being accumulated by Charles E. Myers, MD, director of the American Institute Diseases of the Prostate – as yet unpublished. Myers has made an astute observation that the two drugs could be synergistic, allowing lower doses to be used for the combination. This is turning out to be true in a significant number of patients.

Leukine and Thalidomide

Thalidomide, in combination with leukine or thalidomide alone,  may provide another option for extending the off-time.

At the June 2004 American Association of Clinical Oncologists Meeting, M. Lilly et al (18), gave the results of a phase I trial of leukine and thalidomide. Leukine activates dendritic cells and thalidomide modulates T-cell and NK function. Leukine was given daily for 14 days and then every other day for 3 months. Thalidomide was taken daily starting on day 15 for 3 months total. This small study of 10 hrpca patients determined a maximum tolerated dose of 250mcg of leukine and 100 mg thalidomide. The PSA response rate was quite high – 7/9 patients had an average PSA decrease of 50.4% and 1 patient with soft tissue pca had a 60% decrease in the tumor. Low tumor burden may be important in the duration of response to this treatment. PSA responses were much longer if pre-treatment PSA was under 50ng/mL than if it was greater than 50 (26.4 weeks vs 9.5 weeks).

Thalidomide has anti-prostate cancer properties of its own, including antiangiogenic and immunomodulatory properties (19) and has been tested in several clinical trials either as a single agent or in combination with docetaxel. MJ Drake et al (20), using 100mg/day of thalidomide found a 15% PSA response rate and WD Figg et al (21) using 200mg/day up to 1200mg/day of thalidomide had a PSA RR of 18% (50% decline criteria) while also finding that overall 27% of the patients had a decline of over 40% in PSA. Most recently, WL Dahut et al (22), compared docetaxel(30mg/m2, 3 of 4 weeks) plus thalidomide (200mg/day) with thalidomide (200mg/day) in a randomized phase II trial. The combination tx group had a PSA response rate of 53% and the single agent group’s PSA decline was 37%. Dahut et al also found that the combination arm required anticoagulation to prevent a high incidence of DVTs (23% before anticoagulation and 0% after coagulation.)
 

Leukine and Ketoconazole/hydrocortisone

In a paper presented at the Orlando Prostate Cancer Multidisciplinary Meeting of February 2005, C.J. Ryan et al reported on the interim results of the combination of Leukine(GM-CSF) (250mg/m2, days 1-14 of a 28 day cycle) plus ketoconazole (400mg, orally 3 times/day) with hydrocortisone (20 mg morning, 10 mg evening).  The rationale for this trial was the hypothesis that GM-CSF would augment T-cell response to apoptotic tumor cells and prolong duration of response to ketoconazole.

There were 26 patients in this study and all 26 completed 3 28-day cycles.  PSA responses (>50% decrease) were 69%.  Additionally 54% of the patients had declines > 80%. The most common adverse event was grade 3 fatigue seen in 5 patients. At the time this was presented, the time to progression had not yet been determined.

Conclusions
 

Patients should work closely with their oncologist in understanding how these drugs might be used to extend the off chemotherapy time. The information provided in this paper should help with that. Consider using leukine by itself to extend the time off chemotherapy. Consider also adding accutane or vesanoid since they may provide a synergistic effect when combined with leukine. Lastly, if accutane or vesanoid do not provide an increase in PSA doubling time, thalidomide can be used. In the case of thalidomide, reducing the dose lower than the maximum tolerated dose to 50mg might delay any onset of side effects.  And lastly, consider the leukine/ketoconazole combination described above.

A Precaution from the prescribing information: "Leukine can induce variable increases in WBC and/or platelet counts.  In order to avoid potential complications of excessive leukocytosis(WBC > 50,000 cells/mm3; ANC> 20,000 cell/mm3, a CBC is recommended twice per week during Leukine therapy."  If these levels are exceeded, they recommend interrupting administration or decreasing dose by half.

Author: Howard Hansen
Date: 9/30/2004, last updated 3/22/06

Note: The author is not a medical doctor and cannot render medical advice. As a prostate cancer patient, this was written in an attempt to understand these treatments and how it affects me. I make no claims that this review is definitive, complete or authoritative and I request any contributions to, or clarification of the subject which might contribute to the issue or inquiry. In conjunction with a medical team, every cancer patient must make their own decisions regarding treatment options. Your own medical team's directions should be carefully followed.
 

References
 

(1) TM Beer, et al, Intermittent Chemotherapy in Metastatic Androgen-Independent Prostate Cancer, British J. of Cancer(2003) 89, 968-970.

(2) Nakajima H, Kizaki M, Sonoda A, Mori S, Harigaya K, Ikeda Y., Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells, Blood. 1994 Dec 15;84(12):4107-15.

(3) Rivas CI, Vera JC, Delgado-Lopez F, Heaney ML, Guaiquil VH, Zhang RH, Scher HI, Concha II, Nualart F, Cordon-Cardo C, Golde DW. Expression of granulocyte-macrophage colony-stimulating factor receptors in human prostate cancer. Blood. 1998 Feb 1;91(3):1037-43.

(4) Simmons SJ, Tjoa BA, Rogers M, Elgamal A, Kenny GM, Ragde H, Troychak MJ, Boynton AL, Murphy GP., GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial. Prostate. 1999 Jun 1;39(4):291-7.

(5) Small EJ, Reese DM, Um B, Whisenant S, Dixon SC, Figg WD. Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 1999 Jul;5(7):1738-44. 

(6) Rini BI, Small EJ. Immunotherapy for prostate cancer. Curr Oncol Rep. 2001 Sep;3(5):418-23. Review. PMID: 11489243 and in Rini BI, Small EJ, The potential for prostate cancer immunotherapy, Crit Rev Oncol Hematol. 2003 Jun 27;46 Suppl:S117-25.

(7) Dreicer R, See WA, Klein EA. Phase II trial of GM-CSF in advanced prostate cancer. Invest New Drugs. 2001;19(3):261-5. PMID: 11561685

(8) Rini BI, Weinberg V, Bok R, Small EJ. Prostate-specific antigen kinetics as a measure of the biologic effect of granulocyte-macrophage colony-stimulating factor in patients with serologic progression of prostate cancer. J Clin Oncol. 2003 Jan 1;21(1):99-105. 

(9) Dieckgraefe, B. K. & Korzenik, J. R. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor, Lancet, 2002, 360 (9344): 1478-80.

(10) Kelly WK, Osman I, Reuter VE, Curley T, Heston WD, Nanus DM, Scher HI. The development of biologic end points in patients treated with differentiation agents: an experience of retinoids in prostate cancer. Clin Cancer Res. 2000 Mar;6(3):838-46.

(11) Culine S, Kramar A, Droz JP, Theodore C., Phase II study of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer. J Urol. 1999 Jan;161(1):173-5.

(12) Trump DL, Smith DC, Stiff D, Adedoyin A, Day R, Bahnson RR, Hofacker J, Branch RA., A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis., Cancer Chemother Pharmacol. 1997;39(4):349-56.

(13) 7. Galsky M, Kelly WK., The development of differentiation agents for the treatment of prostate cancer, Semin Oncol. 2003 Oct;30(5):689-97.
 

(14) Shalev, M., et al., Effect of 13-cis-retinoic acid(accutane) on serum prostate-specific antigen levels in patients with recurrent prostate cancer after radical prostatectomy, Clin Cancer Res, 2000, 6 (10): 3845-9.

(15) Ferrari, A. C. et al., 13-cis retinoic acid (accutane) and complete androgen blockade in advanced hormone-naïve prostate cancer patients: report of a phase II randomized study. J Clin Oncol, 2002, 20 (2): 538-44.

(16) Nakajima H, Kizaki M, Sonoda A, Mori S, Harigaya K, Ikeda Y., Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells, Blood. 1994 Dec 15;84(12):4107-15.

(17) Lotan Y, Xu XC, Shalev M, Lotan R, Williams R, Wheeler TM, Thompson TC, Kadmon D. Differential expression of nuclear retinoid receptors in normal and malignant prostates. J Clin Oncol. 2000 Jan;18(1):116-21. 

(18) M. Lilly, E. H. Rowsell, R. Gurrola, H. Ruckle, Phase I trial of sargramostim and thalidomide for treatment of hormone-refractory prostate cancer. ASCO 2004, Abstract No: 4690.

(19) Macpherson GR, Franks M, Tomoaia-Cotisel A, Ando Y, Price DK, Figg WD, Current status of thalidomide and its role in the treatment of metastatic prostate cancer, Crit Rev Oncol Hematol. 2003 Jun 27;46 Suppl:S49-57.

(20) Drake MJ, Robson W, Mehta P, Schofield I, Neal DE, Leung HY.
An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer, Br J Cancer. 2003 Mar 24;88(6):822-7.

(21) Figg WD, Dahut W, Duray P, Hamilton M, Tompkins A, Steinberg SM, Jones E, Premkumar A, Linehan WM, Floeter MK, Chen CC, Dixon S, Kohler DR, Kruger EA, Gubish E, Pluda JM, Reed E, A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer, Clin Cancer Res. 2001 Jul;7(7):1888-93.

(22) Dahut WL, Gulley JL, Arlen PM, Liu Y, Fedenko KM, Steinberg SM, Wright JJ, Parnes H, Chen CC, Jones E, Parker CE, Linehan WM, Figg WD.
Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer, J Clin Oncol. 2004 Jul 1;22(13):2532-9.

(23) C. J. Ryan, J. Rosenberg, B. Rini, T. Nguyen, V. Weinberg, E. Small, A phase II trial of ketoconazole plus granulocyte macrophage colony stimulating factor (GM-CSF) in androgen independent prostate cancer (AIPC).  ASCO 2005 Multidisciplinary Prostate Cancer Symposium; February 17-19, 2005; Orlando, Florida. Abstract No: 296

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