for Hormone-Refractory Prostate Cancer
Is Mitoxantrone a Viable
2nd-Line Chemotherapy for HRPC?
And what might be added to it to
improve its response rate?
by Howard Hansen
Most recent update: 26 August 2009
PSA RR - a decline of PSA of 50% or more. Sometimes called a PR or
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
progressive disease, PSA increase > 25%.
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.
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
Joshua et al (7) and Saad et al (8) both examined the
sequence of mitoxantrone 1st with 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.
Phase and No. of patients
5. Michels, JE et al, Cancer 2006.
35 D to M; 33
M to D.
D(65%) to M(12%)
D(6 mo.) to
M(5 mo.) to
* D(22 mos.) to M(12 mos.)
M(15 mos.) to D(7 mos.)
Docetaxel preferred 1st line
6. Oh WK et al, Urology 2006.
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
M to T
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
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
Prospective, T to M to Ix or T to Ix to M.
T to M(20%), M being 2nd line and M
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
T to M (13 mos.)
T to Ix (12.5
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
** Median interval from start of 1st chemotherapy to
progression after 2nd was 39.9 wks for Mitoxantrone 1st and 38.7 wks for
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
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.
Can be Combined with Mitoxantrone to Improve its Response Rate and Perhaps
enhancing its effectiveness as a second line or third line chemotherapy?
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.
Yet another combination with mitoxantrone is to add
Ixempra which is approved for breast cancer. This is summarized on the
Ixempra page with 5 and 5.1 the references. This
combination is currently in phase II testing as a possible ≥ 2nd line
treatment following taxotere failure.
Table 2. Mitoxantrone
Combined with other drugs such as taxotere, emcyt, ketoconazole,
DN101(calcitriol), gm-csf. (note that DN-101 has never become commercially
available -- you might use HDPC per T. Beer).
Phase and No. of
Other Drugs used.
or Overall RR
MTP or MS
(10) A. Heidenreich et
No: 276, ASCO PCa Mtg, Feb. 2005, Orlando.
II, 97, multi- center.
60 mg/m2 Every 3 wks.
8 mg/m2 every 3 weeks.
PSA RR 71%.
Time to progression
14.4 (4-23) months.
mean survival time was
specific and overall survival were 82% and 78%, respectively.
(11) SL Freeman, et al, ASCO 2003, Abs 1735.
II, 16. 4 21
day cycles. After 4 cycles of chemo, the cycle length was increased to
30mg/m2 days 1 and 8
8 mg/m2 on day 1.
(12) Beer, TM et al, Clin. Can Res 2004.
I, pre-RP high risk patients.
35mg/m2, fixed. 3 weeks out of 4.
3 wks out of 4.
(13) Eklund J et al,
HDK(400mg TID)/HC(20mg, qAM, 10mg qPM.)(also
used 250mg ascorbic acid with keto)
12mg/m2, q21 days
= 70%; Overall RR soft tissue 13%, bone disease 8%.
Median PFS 10 mos. Median Overall survival 18 mos.
(14)Chan, JS et al, ASCO PCa Symp. 2006, Abs. #233.
II, 13 evaluable at time of abstract
DN-101, 180mcg, day before Mitoxantrone.
12mg/m2, q21 days
2 partial response
(both measurable disease and PSA reduction of >50%) and 3 had PSA
(15) Samelis GF et al,
Emcyt, 140mg 3x/day
20mg total dose,
repeated every 2 weeks.
PSA RR was 50% (13
patients); measurable disease RR was 27%.
MDR 9.2 mos.;
MS 15 mos.
(15.1) RJ Amato et al, ASCO GU Sym. 2008.
(trial is on-going)
all failed 1st line taxotere.
GM-CSF (leukine), 250mcg/m2, 14 days on, 7 off.
Ketoconazole, 400mg 3x/day.
12mg/m2 every 3 weeks, maximum cum. dose of 140mg/m2.
15 of 22 evaluable patients had PSA decline
2 patients with LN had CR, majority had bone & soft
The median duration of treatment is 6+ months
(15.2) G. Doshi et al, ASCO 2009, Abstract e16033.
2nd Line Treatment
-, 31 pts; all failed 1st line taxotere, ≤ 2 chemos
GM-CSF (leukine), 250mcg/m2, 14 days on, 7 off.
Ketoconazole, 400mg 3x/day.
12mg/m2 every 3 weeks, maximum cum. dose of 140mg/m2.
8 pts ≥ 50% 5 pts ≥ 80% 7 pts
The median duration of treatment was 6.22 mos(2 mos to 20.5 mos.)
(a) 15.1 was the original abstract in 2008;
15.2 appears to be the final abstract that was published in June 2009 - ASCO.
The PSA response rate would be 20/31 or 68% which is outstanding for a ≥ 2nd
line chemotherapy. The authors also say that the majority of patients had
stabilization of their bone and soft tissue disease plus 2 patients with
lymph node disease had radiographic complete responses. Significant
adverse events included grade III/IV neutropenia, thrombocytopenia, and
nausea. Patients were on study until either the completion of Mitoxantrone
or maximum anti-tumor benefit. Pts continued Ketoconazole/ GM-CSF until
disease progression. PSA was evaluated every 3 weeks and radiographic
studies were performed every 9 weeks.
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."
(15.2) G. Doshi, P. Cen, P. Ramirez, R. Amato, Granulocyte macrophage:
Colony stimulating factor (GM-CSF), ketoconazole, and mitoxantrone as
second-line therapy in patients (Pts) with progressive hormone refractory
prostate cancer (HRPC), J Clin Oncol 27, 2009 (suppl; abstract e16033).
(this is an update of the 2008 information in 15.1)
Patients seem to respond well using mitoxatrone following taxotere failure.
Here's an anecdotal report for one patient.
12/9/2009. DB reports, I have just recently
completed a full course of Mito (140mg/M2) plus HDK/HC (600 mg tid) about
six weeks ago. (You and I discussed this protocol last year,
remember....only I did not use the Leukine combo). It sure worked for me
reducing my PSA from 128 in Oct '08 down to 30.8 in Oct '09. I stayed on
just the Keto/HC only since, but now my PSA result on 12/ 09 /09 on the rise
again to 34.6.
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
What then? Perhaps we can
improve on this by adding other drugs as listed in Table 2.
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.
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.
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 Information
For a more complete list of side effects, visit the
Author: Howard Hansen, 24 January 2007; minor update done 21 August 2009.
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
The following paper by Berry et al is available
on-line. It provides complementary information to what I have written.
See also the following review article which includes a
section on mitoxantone as 2nd line chemotherapy: Berthold DR,
Sternberg CN, Tannock IF, Management of advanced prostate cancer after
first-line chemotherapy, J Clin Oncol. 2005 Nov 10;23(32):8247-8252.
There are other drugs that can be used with
Mitoxantrone to enhance its response rate. One of these is DPPE
(N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene.
This combination produced a PSA RR of 59%. Unfortunately DPPE isn't a
commercially available drug.
(16) Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles
E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW, Phase II trial of
tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate
cancer: high subjective and objective response in patients with symptomatic
metastases, J Urol. 2005 Nov;174(5):1808-13; discussion 1813. [abstract
Another might be silibinin (derived from Milk Thistle.)
A recent in vitro study found a silibinin and mitoxantrone to be synergistic
at doses achievable in humans per an earlier phase I trial of silibinin(17).
Flaig T et al found a maximum tolerated dose of 13g in 3 divided doses
(actually this was silybin-phytosome.)(18). Note: 13g is a large quantity:
The Life Extension Foundation has a 900 gram "mega silymarin" capsule. That
would only require around 4 capsules 3x/day. it's not clear whether or
not what was used in the studies below is the same or equivalent to what is
in these capsules.
(17)Int J Cancer. 2007 Jan 17; [Epub ahead of print]
Silibinin synergizes with mitoxantrone to inhibit cell growth and induce
apoptosis in human prostate cancer cells. Flaig TW, Su LJ, Harrison G,
Agarwal R, Glode LM.
(18)Invest New Drugs. 2007 Apr;25(2):139-46. Epub 2006 Nov 1.
A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer
patients.Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison
GS, Pierson AS, Agarwal R, Glode LM. [abstract
One last combination: Velcade(bortezomib) plus
mitoxantrone. This is being studied in a clinical trial at MD Anderson
(call 713-792-3245 for more information.)