Mitoxantrone(Novantrone®) for Hormone-Refractory Prostate Cancer

And what might be added to it to improve its response rate?

by Howard Hansen

Most recent update: 4/4/08.

Definitions

PSA RR - a decline of PSA of 50% or more.  Sometimes called a PR or partial response.

PFS - Progression-free survival (median). Measured from start of treatment.

OS - Overall Survival (median). Measured from start of treatment.

D - Docetaxel (taxotere).

M - Mitoxantrone (Novantrone).

T - Taxane (taxol or taxotere).

SD - stable disease, PSA decline of < 50% through an increase of 25% or less.

PD - progressive disease, PSA increase > 25%.

Introduction

Mitoxantrone is a United States FDA approved chemotherapy for HRPC.  Most commonly, it is used with prednisone.  The PSA response rate for Mitoxantrone is fairly low (it was 32% in chemo-naive patients in the TAX327 phase III clinical trial which compared taxotere with mitoxantrone (1) and 28-38% in earlier trials (2,3,4). The trials comparing Mitoxantrone/prednisone or Mitoxantrone/hydrocortisone with prednisone or hydrocortisone alone did not find any survival differences between the two arms. The patients in these trials were also chemo-naive.

(1) Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512. This presents the results of the TAX327 Phase III clinical trial which led to FDA approval.

(2) Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756–1764.

(3)Kantoff PW, Halabi S, Conaway M et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17:2506–2513.

(4)Dowling AJ, Czaykowski PM, Krahn MD, Moore MJ, Tannock IF, Prostate specific antigen response to mitoxantrone and prednisone in patients with refractory prostate cancer: prognostic factors and generalizability of a multicenter trial to clinical practice, J Urol. 2000 May;163(5):1481-5.
 

How Does  Mitoxantrone Work?

Mitoxantrone belongs to a general group of chemotherapy drugs known as antibiotics although it isn't used as such due to its high toxicity. Mitoxantrone generally is lumped into a chemotherapy group known as the anthracyclines which includes doxorubicin (Adriamycin). While structurally similar to doxorubicin, it is really an anthracenedione. It inhibits DNA topoisomerase II. It causes inter/intrastrand cross-linking, causes DNA strand breaks -- all of which act to prevent cell division. It is cell cycle phase-nonspecific as opposed to the taxanes which are cell cycle specific (taxanes are mitotic inhibitors.)

Second Line Mitoxantrone

What happens when Mitoxantrone is used as a 2nd line chemotherapy?  Since taxotere was shown to be superior in PSA reduction and survival over mitoxantrone one would expect taxotere to be used as a 1st line treatment, followed by mitoxantrone as a 2nd line treatment.  Four papers have discussed this treatment sequence and their results are summarized in Table 1.

Michels et al(5) did a retrospective analysis of patients receiving both mitoxantrone and docetaxel.  They found that going from Taxotere " Mitoxantrone, the patients had a PSA RR of 12%(when receiving mitoxantrone) and the sequence Mitoxantrone " Taxotere had a PSA RR of 38%(when receiving Taxotere.)  Just to confound matters, the overall survival of these two groups did not significantly differ. Furthermore, 46% of the mitoxantrone patients required a dose reduction, delay or discontinuation because of toxicity when receiving mitoxantrone as a 2nd-line chemotherapy following taxotere. The authors concluded that docetaxel would be the preferred 1st chemotherapy with mitoxantrone used as a 2nd chemotherapy.

Oh et al(6), in another retrospective analysis, examined patients who had been treated with taxanes (taxol, taxotere by themselves or combined with emcyt and/or carboplatin) or mitoxantrone as 1st-line chemotherapy and then had the other chemotherapy as a 2nd-line treatment (T to M or M to T). Taxane based regimens had better PFS whether used 1st or 2nd, but total PFS and OS were similar independent of sequence.  Most patients (50%) had disease stabilization with second-line mitoxantrone.

Joshua et al (7) and Saad et al (8) both examined the sequence of mitoxantrone 1st wit docetaxel 2nd.  Joshua used a weekly docetaxel regimen of 40mg/m2 3 wks out of 4 and Saad used 75mg/m2 every 3 week docetaxel plus prednisone.  Saad reported a PSA RR of 85% for 17 of 20 patients.  This was substantially higher than Joshua reported for his weekly docetaxel. 

Lin et al (9) documented a trial of what happens when using ixabepilone(Ix) or M after primary taxane chemotherapy has failed.  While the authors' conclusion was that both Ix and M only have "modest" activity as 2nd or 3rd line treatments, one should also note that the new, highly touted Ix didn't appear to perform any better than the "old" mitoxantrone. 

Table 1 summarizes the 2nd line (and in one case 3rd line) results.

Table 1. Summary of papers on taxane to mitoxantrone sequences and vice versa.

Study	Phase and No. of patients	PSA RR	PFS(median)	OS(median)	Comments
5. Michels, JE et al, Cancer 2006.	Retrospective, 35 D to M; 33 M to D.	D(65%) to M(12%) M(31%) to D(38%)	D(6 mo.) to M(2-3 mo.)   M(5 mo.) to D(2-3 mo.)	* D(22 mos.) to  M(12 mos.) * M(15 mos.) to  D(7 mos.)	Docetaxel preferred 1st line chemo.
6. Oh WK et al, Urology 2006.	Retrospective, 35 T to M; 33 M to T.	T(68.6%) to M(5.9%)   M(12.1%) to T(60.6%)	** T(17 wks.) to M(6.1 wks.)   ** M(10.1 wks.)to T(16.3 wks.)	M to T 60.8 wks.   T to M 68.4 wks. Not significantly different.	Taxane based regimens had better PFS whether used 1st or 2nd, but total PFS and OS were similar independent of sequence.
7. Joshua AM et al, Intern Med 2005.	Prospective, II, 20 patients. M to D only.	M to D (45%)	From starting D, 5 mos.(.3 to 13 mos.)	From starting D, 13 mos.(1-24 mos). From starting M, 19 mos.	RR and survival comparable to previous D trials(PSA RR range 38-48)
8. Saad F, et al, ASCO 2005.	Prospective, II,30 patients. M to D only.	M to D (85%)	-	> 20 mos. from start of M.	D as 2nd line has comparable tolerability, PSA RR and Pain Reduction as when used as 1st line.
9. Lin AM et al, ASCO 2006, abs 4558.	Prospective, T to M to Ix or T to Ix to M.	T to M(20%), M being 2nd line and M to Ix(12%), Ix 3rd line. T to Ix (17%), Ix being 2nd line and Ix to M(31%), M 3rd line.	Reported as median TP. T to M (2.3 mos.) T to Ix (2.2 mos.)	T to M (13 mos.) T to Ix (12.5 mos.)	M and Ix have only modest activity as used in this trial.

D = docetaxel(taxotere); M = mitoxantrone(Novantrone); Ix = ixabepilone.

T = taxane (taxotere, taxol, and combinations of these with emcyt and/or carboplatin.)

* 22 mos. vs 15 mos. not statistically different.  The overall median survival for all patients after 2nd-line chemotherapy was 9 mos.

** Median interval from start of 1st chemotherapy to progression after 2nd was 39.9 wks for Mitoxantrone 1st and 38.7 wks for taxane first.

5. Michels J, Montemurro T, Murray N, Kollmannsberger C, Nguyen Chi K, First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer: does sequence matter? Cancer. 2006 Mar 1;106(5):1041-6.

6. Oh WK, Manola J, Babcic V, Harnam N, Kantoff PW, Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes, Urology 2006 Jun;67(6):1235-40.
 

7.  Joshua AM, Nordman I, Venkataswaran R, Clarke S, Stockler MR, Boyer MJ,
Weekly docetaxel as second line treatment after mitozantrone for androgen-independent prostate cancer, Intern Med J. 2005 Aug;35(8):468-72.

8. F. Saad, D. Ruether, S. Ernst, S. North, E., Canadian Urologic Oncology Group (CUOG) phase II multi-center study using docetaxel/prednisone in the second line setting for metastatic hormone-refractory prostate cancer in patients progressing after first line mitoxantrone/prednisone, Annual Meeting Proceedings. Journal of Clinical Oncology, 2005 ASCO, Vol 23, No 16S (June 1 Supplement), 2005: 4612.

9. A. M. Lin, J. E. Rosenberg, V. K. Weinberg, W. K. Kelly, M. D. Michaelson, M. Hussain, G. Wilding, M. E. Gross, E. J. Small, Clinical outcome of taxane-resistant (TR) hormone refractory prostate cancer (HRPC) patients (pts) treated with subsequent chemotherapy (ixabepilone (Ix) or mitoxantrone/prednisone (MP), Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: Abstract 4558. Ixabepilone is a synthetic epothilone B analogue that is currently in clinical trials.  Treatments:  M 14 mg/m2 IV q3wks and P 5 mg PO BID or 2) Ix 35 mg/m2 IV q3wks.

What Can be Combined with Mitoxantrone to Improve its Response Rate and Perhaps enhancing its effectiveness as a second line or third line chemotherapy?

Table 2 documents various clinical trials where mitoxantrone has been used in combination with other drugs such as ketoconazole, emcyt, taxotere and DN101(calcitriol).  Assumption -- comparing the PSA RR of the studies in Table 2, to the usual PSA RR of mitoxantrone alone one finds that the combinations give an improved response.  These are likely mostly chemotherapy naive patients.  However, given that mitoxantrone, per Table 1, still has some efficacy as a 2nd line chemotherapy, we can speculate that the combinations will have a higher response rate.  The paper by RJ Amato et al (15.1) gives some indication of this being possible.

Preliminary results from an on-going phase II trial of the combination of mitoxantrone, gm-csf (leukine), and high dose ketoconazole (15.1) provide an additional combination and further support the results of Eklund J et al, but in the 2nd line setting. 

There is another clinical trial looking at the combination of mitoxantrone and gm-csf in the 2nd line setting also (patients have to have failed 1st line taxotere). Go to http://clinicaltrials.gov/show/NCT00477087 for detailed information.  The trial description indicates that this combination may lead to enhanced antitumor activity in HRPC patients.

Table 2. Mitoxantrone Combined with other drugs such as taxotere, emcyt, ketoconazole, DN101(calcitriol), gm-csf.

(10)  A. Heidenreich, C. H. Ohlmann, U. H. Engelmann,  Docetaxel (DOC) and mitoxantrone (MIT) in the management of hormone refractory prostate cancer (hrpca); Abstract No: 276, ASCO PCa Mtg, Feb. 2005, Orlando.  

(11) S. L. Freeman, J. Wesner, J. A. Polikoff,  A phase II study of the combination of docetaxel/mitoxantrone/low-dose prednisone in men with hormone-refractory prostate cancer (HRPC), ASCO Annual meeting 2003; Abstract No: 1735.

 (12) Beer T et al, Clinical Cancer Res, vol. 10, pp 1306-1311, Feb 2004. Phase I Weekly Mitoxantrone and Docetaxel before RP for High Risk PCa. 

 (13) Eklund J, Kozloff M, Vlamakis J, Starr A, Mariott M, Gallot L, Jovanovic B, Schilder L, Robin E, Pins M, Bergan RC,  Phase II study of mitoxantrone and ketoconazole for hormone-refractory prostate cancer, Cancer. 2006 Jun 1;106(11):2459-65.  Note: two patients had received prior taxane-based chemotherapy(taxol and one(possibly both) had partial responses per email with Bergan.  An abstract of earlier results for this trial was given at the ASCO Annual Meeting 2002, abstract 778.

(14) J. S. Chan, T. M. Beer, D. I. Quinn, M. Garzotto, M. Sokoloff, C. W. Ryan, Phase II study of DN-101 (high dose calcitriol), mitoxantrone, and prednisone in androgen-independent prostate cancer (AIPC), ASCO 2006 Prostate Cancer Symposium, Abstract No: 233.  Continuous daily prednisone 10mg.  Max. cycles 12.

(15) Samelis GF, Skarlos D, Bafaloukos D, Kosmidis P, Anagnostopoulos A, Aravantinos G, Dimopoulos MA; The combination of estramustine and mitoxantrone in hormone-refractory prostate cancer: a phase II feasibility study conducted by the Hellenic Cooperative Oncology Group. Urology. 2003 Jun;61(6):1211-5. The most common side effects were neutropenia and  thrombocytopenia.

(15.1) R. J. Amato, M. Dalton, P. Harris, J. Jac, Phase II trial to assess the activity of granulocyte macrophage-colony stimulating factor (GM-CSF), ketoconazole & mitoxantrone in patients with progressive hormone refractory prostate cancer (HRPC),  2008 Genitourinary Cancers Symposium, Abstract No: 174. The abstract notes that, "Significant adverse events included grade 3/4 neutropenia, thrombocytopenia and nausea."
 

Discussion/ Conclusion

Assuming that most patients now are likely to receive taxotere as a first line chemotherapy, then the data for D to M is most relevant. The PSA RR(table 1) for D to M ranges from 6% to 12% and perhaps to as much as 20% if reference (e) is included.

From a patients point of view, while a PSA RR is great, stable disease can also be acceptable. Oh et al included a breakout of stable disease. While the PSA RR was 6% when mitoxantrone followed a taxane, but stable disease rate was approximately 50%.  However, there isn't any information on whether or not these men did any better than those who had a PSA Response.  They are included in the PFS and OS numbers, so overall it probably made no difference.

What then? Perhaps we can improve on this by adding other drugs as listed in Table 2. 

Someday, a study of these combinations will be done as a 2nd or 3rd line chemotherapy.  All a patient can do at this time is discuss them with your oncologist and perhaps try the combination before trying mitoxantrone alone.

In conclusion, mitoxantrone can be used as a 2nd line chemotherapy.  There are combinations using mitoxantrone that might improve PSA RR, PFS and OS  for 2nd line or more chemotherapy, but this has not yet been proven.

Side Effects

One side effect that patients should be aware of is cardiotoxicity.  Mitoxantrone has a recommended maximum cumulative dose of 140mg/m2.  This would be reached after 10 14mg/m2 every 3 week treatments.  It is important to check the left ventrical ejection fraction (LVEF) before and during treatment to lessen the risk of cardiotoxicity. Two different scans are used for this.  Links to pages explaining them in detail are:

MUGA Scan Information http://heartdisease.about.com/cs/otherriskfactors/l/blmuga.htm

Echocardiogram & MUGA Information

http://www.fhcrc.org/patient/support/survivorship/resources/Healthlink.HeartHealth.pdf

http://www.curetoday.com/cureXtra/currentissue/archive/summer2005/index.html

For a more complete list of side effects, visit the chemocare website.

Author: Howard Hansen,24 January 2007.

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.