|
|
Cyclophosphamide
(Cytoxan®)
A possible ≥2nd line
chemotherapy for HRPC
Author:
Howard Hansen
Date: 29
April 2008
Introduction
Cyclophosphamide (CP) is the generic name for Cytoxan®.
It belongs to the class of chemotherapy drugs called "alkylating
agents." It is usually given through a vein by injection or infusion
(intravenous, IV) or by mouth in tablet form, depending upon the
diagnosis.
Alkylating agents are most active in the resting phase (G0) of
the cell cycle. These drugs also work in all phases of
the cell-cycle.
There are several types of alkylating agents, for example,
the Mustard gas derivatives:
Cyclophosphamide, Chlorambucil, and Ifosfamide.
At least for prostate cancer, it
appears that the oral route of administration is most
frequently used. CP is well absorbed when given
orally, it has good bioavailability enabling one to achieve
equal doses whether by the oral or IV routes.
Furthermore, oral administration has less toxicity and
greater ease
of administration compared to IV. Patient compliance is, however,
dependent on the patient actually giving themselves the
drug.
Where might one use this drug
combination? One use would be as a 2nd line
chemo-hormonal therapy. A 2nd possible use might be
during a break or holiday from, say, taxotere 1st line
chemotherapy in order to extend the break from taxotere.
It could also be used as a 1st line chemo-hormonal therapy
to extend the time prior to needing to start taxotere. The
study by (7) using Cyclophosphamide plus prednisone plus DES
could be used as a first line, then, when PSA has decreased
enough (to less than say, 4) dropping the cyclophosphamide
and prednisone and continuing only on DES as a maintenance
therapy.
In general, two different regimes exist
for cyclophosphamide. Continuous low-dose scheduling
has been described as immunostimulatory and/or
antiangiogenic. The low-doses are thought to be able
to lead to enhanced immune response against a
variety of antigens. Murine models showed low dose CP
decreases the number of suppressor or regulatory T cells (Treg)
and directly inhibits the suppressive capability of CD4 + 25
+ Treg cells by enhancing apoptosis and decreasing
homeostatic proliferation. In contrast to the low dose
regime, higher doses of CP lead to cytotoxicity
and immunosuppression.
None of the papers below seems to have
exploited the immunostimulatory aspect of CP.
Clinical Trials
Table 1 lists the various clinical
trials and studies involving oral cyclophosphamide. Table 2 covers some
intravenous clinical trials, one of which used an investigational drug (DPPE).
Table
1. Oral cyclophosphamide combinations.
|
Ref
|
Phase, Number of Patients |
Oral cyclophosphamide (CP) |
Other Drugs Added to CP |
Response Rate.
PSA ≥
50% decrease |
Median Duration of Response |
Median time to progression or median survival |
(1)Cheong
KA et al 2005, ASCO PC symp.
|
Retrospective
study, -, 21 patients.
|
50 mg daily. Oral.
(Metronomic dosing)
|
3 patients rec'd concurrent steriods, 1 of which
had a PSA Response. 4 patients had a PSA
flare response and 2
of these had a PSA response. |
3/17 patients. 1 patient had a flare and
then returned to baseline.
|
-
|
Median time to PSA progression 6.3 months; median
survival 12.9 months
|
(2a)Nelius T et al, ASCO 2007.
(2b) Nelius T et al, Med Onco 2009.
|
-, 17.
All patients had failed 1st line taxotere
|
50 mg daily, until disease progression. Oral.
|
Dexamethasone, 1mg daily, until disease
progression.
|
PSA RR (9 patients median 44.4%), 4 pts
≥
50% and 5 pts < 50%
|
-
|
Median survival was 24 mos. Median survival for
pts with a PSA decrease, 60 mos. (#3)
|
(3) Pecora A, et al. The Prostate J. 2001. #1
|
-, 27 (all chemo-naive)
|
oral, 100mg/m2, days 1-14.
|
Ketoconazole 400mg TID, hydrocortisone 20mg
am/10mg pm both on days 1-28.
|
PSA RR 21/27 (Mean 78%; median 93%). #
|
9 months (range 3 to >96 months).
|
-
|
(4) Lord R, et al, J. Urology 2007. #2.
|
II, 80 (58 evaluable)
chemo-naive.
|
oral, 50mg/m2 continuous in 4 weekly cycles
without breaks for a total of 12 cycles.
|
-
|
34.5% inclusive
of objective and PSA parameters.
|
Median duration of
response 7.5 mos.
Range 3 to 18 mos.
|
Median survival not yet reached.
|
(5) Nicolini A, et al, Biomedecine & Pharm 2004.
|
-, 8.
2 - chemo-naive.
3 - 1 prior chemo.
3 - 2 prior chemos
|
oral, 100-150mg/day alternately until
progression or toxicity.
Mesna 400mg/day po 3 weeks on one off.
|
-
|
PSA %decreases:
31%,
97%,
12%,
45%,
31% in the 5 responders.
|
|
OS(months):
13, 17, 9, 17, 41 in responders measured from
start of cyclophos. |
|
(6) Glode LM et al, Cancer 2003. |
Retrospective,
34. Some not chemo-naive. 32 available for
analysis.
|
oral, 50mg/day. |
dexamethasone, 1mg/day. |
>
80%: 28%.
50-80% decrease: 41%.
<50%:
6%.
|
8
months |
TTP: 9 months. |
|
(7) Hellerstedt et al, Cancer 2003 |
Phase II, 37 pts. Previous chemo allowed. |
100 mg per day on Days 1-20 on 30 day cycle.
|
prednisone 10 mg per day continuously, and DES 1
mg continuously, on a 30-day cycle.
Warfarin 1 mg per day was given as prophylaxis
for thrombosis.
|
15 of 36 pts (42%) had a PSA response. 26% if
prior chemo;
52% if no prior chemo. |
MDR PSA was 9 mos.
|
Overall Median survival was 16.4 mos.
|
|
(13) Raghavan D et al, BJU 1993 |
--, 30 |
Oral CP 100mg/m2 14 days on 14 days off.
|
- |
13 patients had disease stabilization. 6
patients had objective partial remissions. |
- |
Median survival from starting CP was 12.7 mos.
|
|
(12) Daliani, D D, Cancer 2003. |
II,
55(52 evaluable.); 65% had received prior
chemotherapy. |
Oral, 250mg days 1-14. 28 day cycle. |
IV Vincristine, 1mg
daily on days 1,8,15. Oral dexamethasone,
.75mg twice daily on days 1-14. |
PSA: 29%;
Measurable
Disease: 25% had a partial response.
|
Median
progression-free survival duration was 10 weeks,
|
Median
overall survival duration was 10.6 months. |
|
(8) P. U. Moffett
et al, ASCO 2006, Abs.
4647. |
II, 25 |
CP 50 mg/m2 p.o.
|
Etoposide 50 mg/m2 p.o.,
Estramustine 280 mg p.o. on days 1-14 every 28
days.
|
58% |
|
Not been reached; study is ongoing.
|
|
(15) Di Lorenzo G et al,
Cancer Biol Ther. 2007. |
I, 16. Patients had prior docetaxel-based
regimens. |
CP 50mg per day for 28 days = 1 cycle. |
Thalidomide cohort 1(10 patients) = 100mg days.
Cohort 2(6 patients) 200mg 28 days. MTD 100mg
with thalidomide. |
PSA RR 15%; Less than 50% - 1 patient (8%);
overall PSA 23%. |
|
|
( CP = cyclophosphamide; TTP = Time to Progression; MDR
= Median Duration of Response; MTD = maximum tolerated
dose.
# All
responding patients had a drop in PSA level within 6
weeks of the initiation of therapy.
#1 All
patients given a drug free holiday responded on resuming
treatment with CP. "Holidays" ranged from 2-6
months(median 2 months) and were initiated after cycles
of 6-8 months of therapy.
#2
Toxicity of Lord et al (4) trial: CP did not exacerbate
urinary symptoms in any patient, nor was there evidence
of hematuria on urine testing, even after prolonged
administration. Grade 3 lymphopenia was the primary side
effect, occurring in 32.8%.
#3 Five
patients reported a decrease in bone pain after 4 weeks
of treatment.
Table 2. Studies involving intravenous use of
cyclophosphamide.
|
Ref
|
Phase, Number of Patients |
cyclophosphamide (CP) |
Other Drugs Added to CP |
Response Rate.
|
Median Duration of Response |
Median time to progression or median survival |
|
(9) EJ
Small et al, JCO 1996. |
--, 35
Chemo-naive.
|
800-2000mg/m2
IV with g-csf every 21 days.
|
Doxorubicin
IV 40mg/m2 every 21 days. |
PSA:
46%
Measurable
Disease: 33%. |
- |
MST 11 mos.
|
|
(10)LJ Brandes et al, JCO
1995. |
--, 20 |
CP (600 to 800 mg/m2; maximum
dose, 1,500 mg) was administered over the last
20 minutes of DPPE infusion. 4 of 5 weeks. |
DPPE (6 mg/kg) intravenously
(IV) over 80 minutes.
4
of 5 weeks. |
PSA: 50%.
Measurable disease(PR): 71% (5 of
7 patients).
Bone Disease: 1 CR and two PRs.(3
of 16 patients. |
- |
- |
PSA
Response Rate,
PSA ≥
50% decrease. MST - median survival time.
Some Possible Uses of Cyclophosphamide
Most men will receive their first chemotherapy
in the form of docetaxel (taxotere) every 3
weeks. Thus, cyclophosphamide might then
be used as a 2nd line chemotherapy(or greater).
It could also be used while on taxotere to
extend a treatment holiday from the taxotere.
Hellerstedt(7), using cyclophophamide,
prednisone and DES allows the possibility of a
nice segue from all 3 drugs to just DES as a
maintenance therapy. The metronomic dosing
schemes also lend themselves to salvage therapy
at various points of treatment (holidays, 2nd
line, etc.)
Other Related
Studies
The paper by Shaked Y et al (11)
addresses the problem of relapses from metronomic dosing
using xenograph models. Although Shaked et al used a
xenograph model, their concept could be readily
transferred to a patient as they used cyclophosphamide
daily at 20 mg/kg/day and bolus dose (BD) every 3 to 6
weeks. This improved efficacy and significantly delayed
progression of transplanted PC-3 human PCa xenographs.
Anecdotal Reports
Anecdotal reports are not meant to provide proof that something will be
effective in any particular person. They do, however, indicate
that at least some patient has had some success.
TBD.
Conclusions
Ten different papers/protocols are
listed above. Which one is best for any one
patient merits careful consideration of the options
available and their clinical consideration. Certainly
the metronomic therapies look attractive from ease of
use and low toxicities. However, the inclusion of cyclophosphamide is certainly warranted in the treatment
of HRPC.
References
(1) K. A. Cheong, K. Chrystal, P. G. Harper, A single
centre retrospective review of oral cyclophosphamide
in hormone-refractory prostate cancer. Presented at the
2005 Prostate Cancer Symposium, American Society for
Clinical Oncology, 2005, abstract 310. This a very nontoxic therapy
that can be
considered for use in the elderly and frail. Subjects in this study had co-morbidities that made
standard chemotherapy unsuitable.
(2a)
T. Nelius, T. Klatte, W. de Riese, S. Filleur, Clinical
outcome of patients (pts) with taxane-resistant (TR)
hormone-refractory prostate cancer (HRPC) treated with
second-line cyclophosphamide (CP) -based metronomic
chemotherapy. Journal of Clinical Oncology, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No. 18S (June
20 Supplement), 2007: 15647. 3 pts of the progression
group showed a decrease in PSA doubling time. Responses
attributed to metronomic dosing and anti-angiogenesis.
(2b) Nelius T, Klatte T, de Riese W, Haynes A,
Filleur S., Clinical outcome of patients with
docetaxel-resistant hormone-refractory prostate cancer
treated with second-line cyclophosphamide-based
metronomic chemotherapy, Med Oncol. 2009 Apr 14. [Epub
ahead of print]. The authors state that the median
time-to-maximal response was 12 weeks (range 4-36 mos.)
(3) Andrew Pecora, Frank Richter, Anna Pavlick, Vincent
Lanteri, John Scheuch, Stuart Levy, Gene Rosenberg, and
Jack Vitenson; Treatment of Metastatic Hormone
Refractory Prostate Cancer with Ketoconazole,
Hydrocortisone, and Cyclophosphamide, The Prostate
Journal, Volume 3 Issue 2 Page 71 - April/May/June 2001.
and Pavlick AC, Pecora AL, Scheuch J, et al: Treatment
of hormone refractory prostate cancer with ketoconazole,
hydrocortisone and cyclophosphamide. Proc Amer Soc Clin
Oncol 15:698a, 1996.
(4) Lord R, Nair S, Schache A, Spicer J, Somaihah N,
Khoo V, Pandha H., Low dose metronomic oral
cyclophosphamide for hormone resistant prostate cancer:
a phase II study, J. Urol. 2007 Jun;177(6):2136-40;
discussion 2140. Note: 32.8% had grade 3 lymphopenia. No
exacerbation of urinary symptoms, nor evidence of
hematuria on urine testing. As part of their conclusion,
they said, "The efficacy, low toxicity, low cost and
ease of administration of cyclophosphamide justifies
further studies in prostate cancer in combination with
other agents."
The
authors also note that continuous low dose scheduling
may be immunostimulatory and/or antiangiogenic.
(Damber
JE, Chemother Pharmacol 2005;158:354.)
(5)
A. Nicolini et al, Oral Low-Dose cyclophosphamide in
Metastatic Hormone Refractory Prostate Cancer (MHRPC),
Biomedicine & Pharmacotherapy, Vol 58, Issue 8, October
2004, pp 447-450.
Prior chemotherapies were either emcyt or emcyt plus
vinblastine. Overall clinical benefit was 62.5% and
median duration 9 months. Toxicity grade 2 or 3
neutropenia and in 50% pulmonary and urinary infections
(mainly cyctitis with and without hemorrhage).
(6)
Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R.,
Metronomic therapy with cyclophosphamide and
dexamethasone for prostate carcinoma, Cancer. 2003 Oct
15;98:1643-8. Comment in: Cancer. 2003 Oct
15;98:1559-61.
(7)
Beth
Hellerstedt, M.D., et al, Phase II Trial of Oral
Cyclophosphamide, Prednisone, and Diethylstilbestrol for
Androgen-Independent Prostate Carcinoma, Cancer
2003;98:1603–10.
Previous chemotherapy was allowed. 4 of 15 patients
(26%) who had received previous chemotherapy had a
greater-than-50% decline in PSA levels, compared with 11
of 21 (52%) patients who had not received previous
chemotherapy. Median
time to response was 2 cycles. They also found that the
PSA response could be quite gradualwith it taking 1-13
months to see a maximal decrease in PSA level.
(8)
P. U. Moffett, M. A. Choudry, L. A. Ferguson, D. A. Williams,
R. V. La Rocca, F. J. Hendler, D. A. Laber, Update on a phase II
study of cyclophosphamide, etoposide and estramustine in
patients with androgen independent prostate cancer, Journal of Clinical Oncology, 2006 ASCO Annual
Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006:
4647. Toxicity:
Grade 3-4: 36% neutropenia, 12% thrombocytopenia, 5% anemia. Four
patients (27%) developed a thrombotic event. 3 with DVTs, two
spontaneous and one after a 14-hours car trip. One subject with a strong
history of cardiac complications had a myocardial infarction.
Neutropenic fever requiring antibiotic use occurred in 2 patients.
(9) EJ Small, S Srinivas, B Egan, A
McMillan, and TP Rearden, Doxorubicin and dose-escalated
cyclophosphamide with granulocyte colony- stimulating
factor for the treatment of hormone-resistant prostate
cancer, J. Clinical Oncology, May 1 1996: 1617–1625.
(10) Brandes LJ, Bracken SP, Ramsey EW,
N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic
hormonally unresponsive prostate cancer.
J Clin Oncol. 1995 Jun;13(6):1398-403. PSA RR 50%(9/18); PR in soft
tissue 71%(5/7). Abbreviation is DPPE.
(11) Yuval Shaked, Urban Emmenegger,
Giulio Francia, Limor Chen, Christina R. Lee, Shan Man,
Armen Paraghamian, Yaacov Ben-David, and Robert S.
Kerbel, Low-dose Metronomic Combined with Intermittent
Bolus-dose Cyclophosphamide Is an Effective Long-term
Chemotherapy Treatment Strategy, Cancer Res 2005 65:
7045-7051.
(12)
Daliani, D D : Assikis, V : Tu, S M : Papandreou, C N :
Pagliaro, L C : Holtkamp, T : Wang, X : Thall, P F :
Logothetis, C J., Phase II trial of cyclophosphamide,
vincristine, and dexamethasone in the treatment of
androgen-independent prostate carcinoma, Cancer. 2003
Feb 1; 97(3): 561-7. The authors note that: There were
no thromboembolic events, and hematologic and
nonhematologic toxicity was minimal. Vincristine used as
a less toxic alternative of vinblastine. No
patients developed Grade ≥ 3 thrombocytopenia.
(13) Raghavan D, Cox K, Pearson BS,
Coorey GJ, Rogers J, Watt WH, Coates AS, McNeil E,
Grygiel JJ.,
Oral cyclophosphamide for the management
of hormone-refractory prostate cancer, Br J Urol. 1993
Nov;72(5 Pt 1):625-8. 18 of 30 patients had significant
improvement in symptoms of advanced disease.
(14) This website has detailed
information on cyclophosphamide for the patient about to
be
treated by it.
Chemocare on cyclophosphamide.
(15)
Di Lorenzo G, Autorino R, De Laurentiis M, Forestieri V,
Romano C, Prudente A,
Giugliano F, Imbimbo C, Mirone V, De Placido S.,
Thalidomide in combination with oral daily
cyclophosphamide in patients with pretreated hormone
refractory prostate cancer: a phase I clinical trial,
Cancer Biol Ther. 2007 Mar;6(3):313-7. Epub 2007 Mar 6.
Comment in:
Cancer Biol Ther. 2007 Mar;6(3):318-9.
Toxicity: Grade 1-2 constipation, peripheral neuropathy
and fatigue were the most common side effects, noted in
6 (37.5%), 5 (31.25%) and 3 (19%) patients,
respectively.
|
|
[Top]
|
|
