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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;98:160310.  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: 16171625.

(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.

 

 

 

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