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Update of Chemotherapy mainly for taxotere beginning in 2004 - Part I. Taxanes and Mitoxantrone

The following tables summarize abstracts presented at ASCO 2004 or newer publications from 2004 pertaining to chemotherapy. In some cases, earlier abstracts and publications are included for reference. Each table has a list of references pertaining to that particular table. When new data or publications come out, this will be updated.

In general, toxicities have not been included in this paper. They can be found in the abstracts and papers themselves. In some cases, unique side effects are mentioned. Another item not included are the pre-medications used with various chemotherapies. Typically with taxotere, a pulsed dose of dexamethasone is used(e.g., 8mg the day before, 8 mg day of and 8 mg the day after taxotere), but the amount varies considerably (e.g., as low as zero to possibly as much as 60mg) depending on the dose schedule of the taxotere.

It should be noted that in almost all cases dexamethasone is given in a pulsed mode -- either the day of chemotherapy or the day before, day of and day after. This has been shown to not affect PSA. See Weitzman AL, et al, Dexamethasone Does Not Significiantly contribute to the Response Rate of Docetaxel and Estramustine in Androgen-Independent Prostate Cancer, J. Urology 163:834-837, 2000. They gave patients 20mg for 3 days every 3 weeks and no patient had a ≥ 50% PSA decline after dexamethasone and the median PSA increase was 47%. Daily administration of low dose dexamethasone has shown PSA responses. For example, Storlie had a 61% RR with 2.25mg daily dexamethasone.

Definitions

PSA-RR – A decrease of more than 50%, sustained for > 4 weeks.
M-RR – Measurable Disease Response Rate.
MD - Measurable Disease (bone mets are not considered measurable).
PR - partial response in measurable disease.
CR - complete response in measurable disease.
MDS - Median Duration of Survival.
MTP – Median Time to Progression.
MS – Median Survival.
OS – Overall Survival.
TID - three times a day.
BID - twice a day.
qd - every day.
Q (or q) - every as in every 3 weeks (q 3 weeks or q3 w).

There is also interest in combining new biological response modifiers with various chemotherapeutic agents. The following is a list of some of these with their generic and brand names. We will include these drugs in an upcoming paper.

Herceptin = Trastuzumab
Gleevec (STI-571) = Imatinib Mesylate. PDGFR is present in the majority of prostate cancers with bone metastases and may be a valid therapeutic target.
Tarceva = erlotinib, targets a molecule called epidermal growth factor receptor.
Iressa = gefitinib, targets a molecule called epidermal growth factor receptor.
Velcade = bortezomib
Trisenox (arsenic trioxide). Activates proteins that cause tumor cell death and downregulates Bcl-2, a protein that protects cells from dying. Add vitamin C to potentiate its effects. Some possible combinations are: Trisenox/velcade/dexamethasone and Trisenox/taxotere.

Benchmark Taxotere Phase III trials. Tax327 and SWOG 99-16 were phase III trials that were completed and published in 2004. They serve as benchmarks for combination treatments. Highlighted in yellow is the FDA approved dose and schedule for taxotere. An industry website on taxotere covers the following information and it might serve as a complementary site of information about taxotere. This is from Medscape so you may have to register to access it.

"Taxotere® Is the Only Approved First-line Therapy with a Proven Survival Benefit for Metastatic Androgen–Independent Prostate Cancer (mAIPC)
» Taxotere® demonstrates significant overall survival benefit at 21 months and at 3-year follow-up
» Taxotere® Safety Data
» Patient Characteristics
» Conclusions

Reference	Phase and No. of Patients	Taxotere (Docetaxel)	Prednisone	Emcyt	PSA-RR	M-RR	MTP or MS
(1)Tannock et al, NEJM 2004. See also (3)	III, 335	75mg/m2 day 1 of 21 day cycle. (a)	5mg BID qd	-	45% with a median duration of 7.7 mos.	12% (141)	MDS 18.9 mos. MTP 7.7 mos Men with minimal symptoms had median survival of 25.6 mos. & symptomatic patients (median, 17.1 months survival)
(1)Tannock et al, NEJM, 2004.	III, 334	30mg/m2, days 1, 8, 15, 22 and 29 of a 6 week cycle. (b)	5mg BID qd	-	48% with a median duration of 8.2 mos.	8% (134)	MDS 17.4 mos. MTP 8.2 mos
(2)Petrylak et al, NEJM 2004.	III, 338	60mg/m2 day 2, q21 days. Also, 60mg dexamethasone in 3 oral divided doses starting evening before and completed prior to taxotere.	5mg BID qd	280mg TID, days 1-5. (c)	50% (155/309 patients).	PR in 17% (17/103 patients)	Median OS 17.5 mos, MTP 6.3 mos.

(a) In this arm, patients took dexamethasone 8mg 12 hours, 3 hours and 1 hour before docetaxel infusion (oral). 24mg total.

(b) In this arm, patients took dexamethasone 8mg 1 hour before docetaxel infusion

(1)Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators, Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer, N Engl J Med. 2004 Oct 7;351(15):1502-12.

(2) Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer; N Engl J Med. 2004 Oct 7;351(15):1513-20.

(3) Berthold DR, Pond GR, Roessner M, de Wit R, Eisenberger M, Tannock AI; on behalf of the TAX-327 investigators, Treatment of Hormone-Refractory Prostate Cancer with Docetaxel or Mitoxantrone: Relationships between Prostate-Specific Antigen, Pain, and Quality of Life Response and Survival in the TAX-327 Study, Clin Cancer Res. 2008 May 1;14(9):2763-2767.

Further analysis of TAX 327 has been carried out by Terthold DR et al (3).

They determined that at baseline 374 of 815 men assessed for QOL had major pain. 92% of the 374 men had substantial impairment of QOL. Only 75% of those without major pain had substantial impairment of QOL.
Men with minimal symptoms had prolonged survival (median 25.6 months). Symptomatic patients (median, 17.1 months survival and these men were more likely to have initial deterioration of QoL if treated with weekly docetaxel. PSA response and pain response, but not QoL response, were independently associated with survival in landmark analysis.
Symptoms other than pain contribute to impaired QoL in men with hormone-refractory prostate cancer.
Median times to PSA and pain response were 44 and 27 days, respectively; some men had initial increase in serum PSA before subsequent decline.
Early increases in serum PSA (up to 12 weeks) should be ignored when determining response or progression.

The FDA has approved the every 3 week taxotere with prednisone because of the survival benefit. There may be patient friendlier alternatives. Stephen Strum MD recently posted the following to P2P when answering a patient: "Stephen Strum, MD> I have gone back and forth from every 3 week to weekly for Taxol (paclitaxel) & for Taxotere (docetaxel) and every time the patient's report the QOL (Quality of Life) is dramatically better for the weekly. In other tumor types the weekly regimen has been more effective as well. Only in PC has the every 3 week regimen showed a small, but statistically significant edge in median survival.

In another P2P post he indicated: "I rarely if ever use single agent taxane therapy; be it Taxotere or Taxol. I usually combine the taxane with Carboplatin and often some form of estrogen such as Emcyt or DES or estradiol. One option is to go with a weekly lower dose Taxol (or taxotere) regimen and add low dose Carboplatin at a flat dose of 200mg per week. I usually give 4 weeks in a row and then pending CBC give a week or perhaps 2 weeks rest. If the CBC is very good and no major drop in platelets, I may go 5 weeks in a row and a one week rest period. Weekly Taxol or weekly Taxotere is a far friendly regimen then every 3 weeks. Patients handle this much better."

For a long list of possible side effects, see drugs.com's page on taxotere side effects. For example, they have for dermatological side effects the following, "Dermatologic side effects including reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face or thorax (and usually associated with pruritus) have been reported. Severe hand and foot syndrome has been reported. Severe nail disorders (2.6%), alopecia, and localized erythema of the extremities with edema followed by desquamation have also been reported. Very rare cases of cutaneous lupus erythematosus have been reported. One case of supravenous discoloration of the skin due to docetaxel treatment has been reported."

Table 1. Taxotere(Docetaxel) plus Carboplatin and with or without

Estramustine Phosphate (Emcyt).

Reference	Phase, No. of patients	Docetaxel	Carboplatin	Emcyt (b)	PSA-RR >50%	M-RR	MTP or MS
WK Oh et al (1), ASCO 2004, # 4656.	I / 25	Day 2, Weekly 3 of 4 weeks. 20, 25, 30, 36, 43 mg/m2	AUC 5	140mg po TID, days 1-5, 8-12, 15-19	60% for All; 75% at 43mg /m2	3 of 14 had PR (21%)	MS: 14.6 months.
(2) MH Tay, et al, ASCO 2004, Abstract 4679 (a)	- / 4	Q 3 week, 60-70mg/m2	AUC 4	-	3 of 4	-	OS: >36, 20, 63.
(3) WK Oh, et al, CALGB 99813, Cancer 2003;98:2592-8	II / 34	Q 3 week, 70mg/m2, day 2. Used g-csf support.	AUC 5, day 2 following taxotere.	Emcyt 240mg tid, days 1-5	68% (23 of 34 patients)	11 of 21 patients, 52% (PR+CR)	MDR PSA 10 months. MDR Measurable 6 months.

(a) Prior treatments include D alone in patient 1, MP, epothilone analogue and DE in patient 2 and DE with bevacizumab in patient 3. This study indicates that adding carboplatin can continue a response.

(b) Taking Emcyt , empty stomach 1 hr before, 2 hr after meals.

(1) W. K. Oh, E. Hagmann, J. Manola, D. J. George, T. D. Gilligan, M. R. Smith, D. S. Kaufman, P. W. Kantoff, A phase I study of estramustine, weekly docetaxel and carboplatin (EDC) chemotherapy in patients with hormone refractory prostate cancer (HRPC), ASCO 2004, Abstract 4656.

(2) M. H. Tay, D. J. George, T. D. Gilligan, S. M. Kelly, L. Appleby, M.-E. Taplin, P. G. Febbo, P. W. Kantoff, W. K. Oh, Docetaxel plus carboplatin (DC) may have significant activity in hormone refractory prostate cancer (HRPC) patients who have progressed after prior docetaxel-based chemotherapy, ASCO 2004, Abstract 4679.

(3) WK Oh et al, A Phase II Study of Estramustine, Docetaxel, and Carboplatin with Granulocyte-Colony-Stimulating Factor Support in Hormone-Refractory Prostate Carcinoma, CLGB 99813; Cancer 2003;98:2592-8.

Table 2. Docetaxel in combination with high dose calcitriol and with or without Estramustine Phosphate (Emcyt). (updated 4 Feb 2008.)

Reference	Phase No.	Docetaxel	HD Calcitriol	Emcyt			PSA-RR >50%	M-RR	MTP or MS
(1) NM Tiffany, et al, J Urology 2005 (a), (b)	I/II 24 11 chemo-naïve; 13 prior taxotere	Q 3 week, 60 mg/m2, 70 mg/m2 after cycle 1.	60 mcg. Not dosed based on body weight.		Emcyt 280 mg TID, days 1-5	Chemo-naïve: 55% (6 of 11); 1 prior taxotere 9% 1 of 11		-	-
(2) TM Beer, et al, JCO, Vol 21,2003.	II, 37, all chemo-naïve.	Q weekly, day 2 for 6 weeks of 8 week cycle. 36mg/m2.	.5 mcg/kg on day 1.			30 of 37 (81%).		8/15 (53%) had partial response.	MTP 11.4 mos., MS 19.5 mos., OS at 1 year 89%.

(a) 60mcg calcitriol is a much higher dose than the usual .5mcg/kg of body weight previously used for weekly dosing.

(b) Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Four patients had thromboembolic complications.

(1) Tiffany NM, Ryan CW, Garzotto M, Wersinger EM, Beer TM, High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study, J Urol. 2005 Sep;174(3):888-92. This was published earlier in abstract form at ASCO 2004, Abstract 4678.

(2) Tomasz M. Beer, Kristine M. Eilers, Mark Garzotto, Merrill J. Egorin, Bruce A. Lowe, W. David Henner, Weekly High-Dose Calcitriol and Docetaxel in Metastatic Androgen-Independent Prostate Cancer; Journal of Clinical Oncology, Vol 21, Issue 1 (January), 2003: 123-128.

Calcitriol has many interesting properties. Of relevance here is it role as a chemotherapy sensitizing agent. A list from pre-clinical trial studies includes:

induces cell cycle arrest (G0/G1) and differentiation. (Note: G0 is the resting phase and G1 is the portion of the cell cycle when RNA and protein synthesis production starts increasing. )
inhibits proliferation of multiple cancer cell lines.
downregulates genes that inhibit apoptosis.
decreases invasiveness and inhibits angiogenesis.
shows synergy with several cytotoxic agents.

Pre-clinical models have their limitations as shown by the study of high dose calcitriol plus carboplatin where the results did not show any real improvement over carboplatin alone. See Beer TM, Garzotto M, Katovic NM. High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer. Am J Clin Oncol. 2004 Oct;27(5):535-41.

Table 3. Docetaxel in combination with Ketoconazole and

with or without Estramustine Phosphate (Emcyt).

Reference

Phase

No.

Docetaxel

Ketoconazole

Emcyt

PSA-RR

>50%

M-RR

MTP or MS

(1) WD Figg et al, ASCO 2003, Abstract 1731

(a)

I, 12

3 of 4 weeks, 5mg/m2 MTD with this dose of ketoconazole

Ketoconazole,

400mg TID + HC 20mg/10mg

5 of 10 (50%)

(2) PJ Van Veldhuizen, et al, Cancer 2003.

I, 26

Q21 Days, MTD 55mg/m2

Ketoconazole, 400mg BID

(a) hepatic toxicity. Going to lowering keto dose, escalating taxotere dose.

(1) W. D. Figg, Y. Liu, M. R. Acharya, J. L. Gulley, P. M. Arlen, M. Lewis, H. L. Parnes, C. C. Chen, E. Jones, W. L. Dahut; A phase I trial of high dose ketoconazole plus weekly docetaxel in metastatic androgen independent prostate cancer; ASCO 2003; Abstract 1731

(2) Van Veldhuizen PJ, Reed G, Aggarwal A, Baranda J, Zulfiqar M, Williamson S., Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma: a phase I and pharmacokinetic study; Cancer. 2003 Nov 1;98(9):1855-62.

Table 4. Docetaxel in combination with Celebrex and

with or without Estramustine Phosphate (Emcyt).

Reference

Phase

No.

Docetaxel

Celebrex

Emcyt

PSA-RR

>50%

M-RR

MTP or MS

(1) B. Kasimis, et al; ASCO 2004, abstract 4616.

II, 18

3 of 4 weeks, 30mg/m2

400mg po BID

11/17

(64.7%)

5/ (2CR's + 3PR's) (29.4%); SD in 5pts(29.4%)

(1) B. Kasimis, J. Cogswell, S. Hwang, V. Chang, M. Llorente, I. Boholli, S. Srinivas, E. Morales, C. Davis, M. Blumenfruchtl; Phase II trial of docetaxel (D) and high-dose celecoxib (C) in patients (Pts) with hormone resistant prostate cancer (HRPC); ASCO 2004, Abstract No: 4616

Table 5. Docetaxel in combination with Mitoxantrone and with or without

Estramustine Phosphate (Emcyt).

Reference

Phase

No.

Docetaxel

Mitoxantrone

Emcyt

PSA-RR

>50%

M-RR

MTP or MS

(1)Heidenreich, A, et al, ASCO 2003, Abstract 1655.

II, 72

Q 3 weeks; 60mg/m2

8 mg/m2.

42 (62%); 15 (22%) stable PSA.

(1) A. Heidenreich, S. Carl, S. Gleissner, O. Moormann; Docetaxel (DOC) and mitoxantrone (MIT) in the management of hormone-refractory prostate cancer (HRPC), ASCO 2003, Abstract 1655.

There are also two other abstracts on this combination from the AUA 2003 meeting:

Heidenreich,Axel et al, Mitoxantrone and Docetaxel, AUA 2003 abstract # 1491. Asymptomatic hrpca men with rising PSAs. This is the same study as in (1).

Beer TM et al, AUA 2003 abstract # 1662, mitoxantrone/docetaxel before RP for high risk men. MTD was 35mg/m2 taxotere with 4mg/m2 mitoxantrone on a 3 weeks out of 4 dosing schedule.

Table 6. Docetaxel in combination with Estramustine Phosphate (Emcyt).

Reference	Phase and no. of patients	Docetaxel	Emcyt	PSA-RR >50%	M-RR	MTP or MS
(1) K Miller et al. ASCO 2003, Abstract 1660. (a)	II, 49	35mg/m2 3 of 4 weeks on days 2, 9, 16.	140mg TID, days 1-3, 8-10, 15-17.	32/44 (73%) patients achieved a partial PSA response, and 10 patients showed a complete PSA decline (PSA normalization). Pain decreased by >50% in 26 patients.	-	-
(2) R. Birch et al, ASCO 2004, Abstract 4622.	IIb, 62, split arm A and B. Chemo-naïve.	Arm A: D 36 mg/m2 IV day 2, 9, 16, 23, 30, 37 q 8 wks	Arm A: E 280 mg/m2 day 1-5 and day 22-26 PO	11/21 evaluable patients (52%) in arm A.		Median overall survival was 16.4 months in arm A
(2) R. Birch et al, ASCO 2004, Abstract 4622.	IIb, 62, split arm A and B. Chemo-naïve.	Arm B: D, 70 mg/m2 IV day 2 q 3 weeks.	Arm B: E 280 mg/m2 day 1-5 PO.	19/29 evaluable patients (66%) in arm B.		Median overall Survival, 13.2 months in arm B
(3)JC Eymard, et al. ASCO 2004, abstract 4603.	II, 92, randomized to 48 in arm A and 44 in arm B.	Arm A (70 mg/m²IV over 1 hour d1 q3weeks	560 mg/d PO starting 1 day prior to D, for 5 consecutive days).	PSA decrease >50%: 68%; PSA decrease >75%: 36%.	MD: 40 pts. PR 18.2% (Arm A)	Median PSA Response duration, 6 mos. MTP 5.7 mos (range 4.7-5.8)
(3)JC Eymard, et al. ASCO 2004, abstract 4603.	II, 92, randomized to 48 in arm A and 44 in arm B.	Arm B (75 mg/m² IV over 1 hour d1 q3w)	-	PSA decrease >50%: 29%; PSA decrease >75%: 16%	MD: 40 pts. PR 16.7% (Arm B).	Median PSA Response duration, 6 mos. MTP 2.8 mos (2-6.9)
(3) DM Saverese et al, CALGB 9780. J Clin Oncol. 2001 May 1;19 (9):2509-16	II, 46	70mg/m2 q 3 weeks. Hydrocortisone qd 30mg am, 10mg pm.	10mg/kg/d total dose divided TID, days 1-5	30/44 68%	12/24 50% (CR (13%)+ PR (38%)). Median PSA decline of 99.5%	Median Overall survival 20 mos., MTP 10 mos for patients w/MD and 7 mos bone only.
(4) VJ Sinibaldi, Cancer 2002.	II, 42. 10 (25%) had previous chemotherapy	Q21 days, 70mg/m2	280 mg orally every 6 hours × 5 doses) every 21 days. Total dose is 1400mg over 24 hours. 0-6-6-6-6 hr intervals.	18/40, 45%	4/20, 20% PR	MTP 4 mos. MS 13.5 mos for all patients.

(a) they don’t mention the results for a PSA RR >50%.

(1) K. Miller, U. Steiner, S. Machtens, B. Backhaus, M. Siegsmund, M. Johannsen, C. Wulfing, Combination chemotherapy with weekly docetaxel and intermittent estramustine in patients with hormone-refractory prostate cancer (HRPC): A multicenter phase II study; ASCO 2003, Abstract No: 1660.

(2) R. Birch, L. Kalman, L. Holt, B. Graham, B. Wheeler, L. Schwartzberg, Randomized phase IIb trial comparing two schedules of docetaxel (D) plus estramustine (E) for metastatic hormone refractory prostate cancer (HRPC); ASCO 2004, Abstract No: 4622.

(3)J.-C. Eymard, F. Joly, F. Priou, A. Zannetti, A. Ravaud, P. Kerbrat, M. Mousseau, B. Paule, F. Touze, E. Ecstein-Fraisse; Phase II randomized trial of docetaxel plus estramustine (DE) versus docetaxel (D) in patients (pts) with hormone-refractory prostate cancer (HRPC): A final report; ASCO 2004, Abstract 4603.

Note: Prophylactic warfarin (1mg/d PO) was given continuously in Arm A.

(4) Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, Hussain A, Small EJ, Vogelzang NJ; Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B.J Clin Oncol. 2001 May 1;19(9):2509-16.

Note on patient entry demographics: Location of metastases(a patient may have had more than one site).

Bone: 37(80%); Lymph node involvement: 23 (50%); Lung: 4 (9%); Liver: 2 (4%). Measurable disease (mostly lymphadenopathy: 24 (52%).

Note on thrombosis events: 4 (9%), 1 arterial embolism, 1 DVT, 2 superficial venous thrombophlebitis.

(5)Sinibaldi, Victoria J.; Carducci, Michael A.; Moore-Cooper, Sandra; Laufer, Menachema; Zahurak, Marianna; Eisenberger, Mario A., Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma; Cancer 2002;94:1457–65.

Table 7. Docetaxel in combination with Avastin and with or without Estramustine Phosphate(Emcyt). Avastin is bevacizumab (a humanized murine monoclonal antibody to the vascular endothelial growth factor, or anti-VEGF). A phase III version of this may have started, with q 3 weekly taxotere and prednisone plus avastin. 850 patients planned.

Reference Phase and No. of patients Docetaxel Avastin (beva-cizumab) Emcyt PSA-RR >50% M-RR MTP or MS

(1)J. Picus et al, CALGB 90006, ASCO 2003, abstract 1578 II, 79.
Chemo-naive.
70 mg/m2 IV on day 2, and repeated every 21 days. 15 mg/kg of B on day 2 280mg po TID for days 1-5 79% 58% TTP: 9 mos

(1) J. Picus, S. Halabi, B. Rini, N. Vogelzang, Y. Whang, E. Kaplan, W. Kelly, E. Small; The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006; ASCO 2003, Abstract No: 1578.

Note on toxicity: No major bleeds occurred, one patient died of mesenteric vein thrombosis, and one other patient had a deep vein thrombosis. One patient had a stroke. Another patient died from a perforated sigmoid colon thought to be unrelated to treatment.

Table 8. Taxotere (Docetaxel) in combination with Xeloda (capecitabine) and with or without Estramustine Phosphate (Emcyt). Xeloda (capecitabine) is a pro-drug (chemical that turns into the active drug once it is in the circulation) of 5-FU, a very potent chemotherapeutic that is also very toxic. Capecitabine seems to be able to get the same level of effectiveness as 5-FU without much of the gastrointestinal toxicity.

Reference	Phase and No. of Patients	Docetaxel	Xeloda (capecitabine)	Emcyt	PSA-RR	M-RR	MTP or MS
(1)J. Ferrero, et al, ASCO 2004, Abstract #4624.	II, 23 of 50 planned patients. Prior emcyt use allowed.	35mg/m2, days 1, 8, 15	1250mg/m2/day in 2 divided doses from day 5 to 18 of each 28 day cycle.	-	Biological response was observed in 17 pts after the 2^nd cycle and in 7 pts after the 4^th cycle. Seven pts (41.2%) exhibited a PSA decrease of >50% after the 2^nd cycle and 5 pts (71.4%) after the 4^th cycle.	-	-
(2) R Morant, et al., BJC 2004.	II, 25	-	1250 mg m(-2) orally twice daily on days 1-14 every 21 days. Based on toxicity data, they recommend a lower starting dose of 1000 mg x m2 orally twice daily.	-	3 (12%); response duration was 12, 17 and 32 weeks.	-	median time to tumour progression of all patients was 12 weeks

(1)J. Ferrero, J. F. Berdah, E. Chamorey, S. Oudard, S. Dides, G. Lesbats, G. Cavaglione, P. Nouyrigat, C. Foa, P. Guillet, R. Kaphan; A combination docetaxel-capecitabine in patients (pts) with hormone refractory advanced prostate cancer. ASCO 2004, abstract 4624.

Two other references on Xeloda as a single agent for hrpca are:

(2) Morant R, Bernhard J, Dietrich D, Gillessen S, Bonomo M, Borner M, Bauer J, Cerny T, Rochlitz C, Wernli M, Gschwend A, Hanselmann S, Hering F, Schmid HP.; Capecitabine in hormone-resistant metastatic prostatic carcinoma - a phase II trial; Br J Cancer. 2004 Apr 5;90(7):1312-7. They concluded that xeloda should be combined with vinorelbine or docetaxel to be more effective.

(3) El-Rayes BF, Black CA, Ensley JF., Hormone-refractory prostate cancer responding to capecitabine; Urology. 2003 Feb;61(2):462. This is a case report. 5 months of Xeloda resulted in a complete clinical response.

Table 9. Taxotere + Navelbine(vinorelbine).

Vinorelbine, a semisynthetic vinca alkaloid, and docetaxel, a semisynthetic taxane, are active single agents in hormone-refractory prostate cancer and have demonstrated synergy in tumor cell lines and animal models. They both are anti-microtubular. Tumors are sensitized to taxanes by increasing the percentage of tumor cells in the G2/M phase of the cell cycle and vinorelbine is capable of G2/M arrest, so the combination may create a salvage treatment also. Vinorelbine might also be combined with taxol.

Reference	Phase and No.of patients	Taxotere	Navelbine (vinorelbine)	Emcyt	PSA-RR	M-RR	MTP or MS
(1) AJ Koletsky et al; Cancer J. 2003. (a)	II, 21 Chemo-naive.	25 mg/m2 after vinorelbine.	vinorelbine, 20 mg/m2, followed by docetaxel on days 1 and 8 of a 21-day cycle.	-	19 patients were evaluable. > 75%, 8 patients; ≥ 50% to ≤ 75%, 3 patients; < 50%, 7 patients	5 had MD, 3 evaluable, 1 CR + 2 PR.	-
(2)CJ Sweeney et al, Ann. Onco. 2002. (b)	II, 23	-	Weekly 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy). After 8 weeks of therapy the combination was given every other week.	280 mg orally TID for 3 days (the day before, the day of and the day after vinorelbine infusion).	15/21 (71%)	1/8 (12.5%) PR.	MTP (serologic) 3.5 mos. Estimated MS 15.1 mos, actual 1 yr overall survival 71%.
(3) S Goodin et al, ASCO 2002, abstract 2459.	II, 30 With and without prior chemotheapy(c). g-csf support days 2-6, 9-13.	60mg/m2 day 1	15mg/m2 days 1 and 8 of 21 day cycle.		20 mean decrease 57.1% (25.8-90.6%) Chemo-naive: 7(44%) >50% decrease and 5 had stable disease. Prior chemo: 4/14 (29%) demonstrated a > 50% decrease in PSA (2 that progressed on prior chemo and 2 with prior adjuvant chemo).	-	Mean duration of PSA response 6.1 mos(1-18 mos).
Other dosing schedules	None; tailored to the patient.	2nd 20mg/m2 weekly.	1st 10mg bolus. gm-csf support.	-	-	-	-
		20mg/m2 3 of 4 weeks or 2 wks on/1 off, repeat q21 days.	20mg/m2 3 of 4 weeks or 2 wks on/ 1 off repeat q21 days.	-	-	-	-
		25mg/m2 day 3.	5-10mg/m2 x 3 days.	-	-	-	-

(a) g-csf was used as needed.

(b) 48% lower extremity edema and 17% thromboembolic events (emcyt probable cause). No indication of anticoagulation.

(c) 14 patients had prior chemotherapy; 9 had progressed on chemotherapy of which 5 with prior taxane and 5 had received chemotherapy in the adjuvant setting of stage D0 disease.

(1) Koletsky AJ, Guerra ML, Kronish L., Phase II study of vinorelbine and low-dose docetaxel in chemotherapy-naive patients with hormone-refractory prostate cancer, Cancer J. 2003 Jul-Aug;9(4):286-92. Erratum in: Cancer J. 2003 Sep-Oct;9(5):1 p following table of contents.

(2) Sweeney CJ, Monaco FJ, Jung SH, Wasielewski MJ, Picus J, Ansari RH, Dugan WM, Einhorn LH., A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer., Ann Oncol. 2002 Mar;13(3):435-40.

(3) Susan Goodin, Kamakshi V Rao, Elizabeth A Engle, Michael Kane, Terry Capanna, Marie Ciardella, Mary B Todd, Robert S DiPaola, A phase II study of docetaxel and vinorelbine in hormone refractory prostate cancer (HRPC) with and without prior chemotherapy; 2002 ASCO Annual Meeting, Abstract 2459.

There are other possible combinations with vinorelbine as discussed in the following paper:
(4) Willi Kreis, A. Calabro, D.R. Budman, L.M. Adams, North Shore University Hospital, Manhasset, NY.
Synergy of Navelbine (Vinorelbine) with Conventional Chemotherapeutic Agents in Human Prostate Cancer Cell Lines in Vitro. 2375, year 2001. They found vinorelbine was synergistic with docetaxel or doxorubicin and suggested that vinorelbine in combination with anthracyclines and anti-tubulin agents was warranted.
The paper indicates possibilities, not clinical data.

Table 10. Taxotere (Docetaxel) and Thalidomide with or without Estramustine Phosphate (Emcyt).

Reference Phase and No. of Patients Taxotere Thalidomide Emcyt PSA-RR MD-RR MTP or MS

(1)RC Frank et al, ASCO 2004, abstract 4681. (a) II, 12 as of abstract.
6 months of TET, followed by 6 mos thalidomide alone as maintenance.

25mg/m2 3 of 4 weeks. 100 or 200mg as tolerated. 140mg po tid, day before, day of and day after taxotere. >50% 6/9 (67%), >75% in 4/9 (44%), and normalized in 2/9 (22%). 5 pts with measurable disease, 2 had PR (40%) and 2 SD. -

(2)WL Dahut et al, JCO 2004.
(b)

II, 75, chemo -and thalidomide

naive.
30mg/m2 3 of 4 weeks, 25 patients.

-

- 37% (9/24) 27% (3/11) PR. Median PFS, 3.7 mos. At 18 mos, OS 42.9%

30mg/m2 3 of 4 weeks. 50 patients. 200mg qd - 53% (25/47)
(c)
35% (7/20) PR. Median PFS, 5.9 mos. At 18 mos, OS 68.2%.

(a) 2mg coumadin/day was used for prophylaxis against clots. Metastases were present in bone in 10/12 (83%) and in lymph nodes in 7/12 (58%). Two patients entered the maintenance phase: one completed 6 months and experienced an additional 9 months of stable disease, the other relapsed after 4 months on Thal.

(b) Low-molecular weight heparin enoxaparin (40mg subq) was offered to patients in the taxotere/thalidomide arm due to 'unexpectedly' high number of thromboembolic events. This was begun after 43 patients had been enrolled and 12 of these 43 had thromboembolic events. The addition of lmwh resulted in no further such events.

(c) In this combination arm, 1 patient progressed in soft-tissue only. Progression in all other cases involved PSA as well as bone and/or soft tissue.

(1) R. C. Frank, A. Coscia, L. Versea, N. Cohen, R. Zelkowitz, A. Ruskin, A. Skeris, P. Dodds, K. Nair; Norwalk Hospital, Norwalk, CT; Stamford Hospital, Stamford, CT; Low dose docetaxel, estramustine and thalidomide followed by maintenance thalidomide for the treatment of hormone refractory prostate cancer (HRPC): A phase II community based trial; ASCO 2004, abstract 4681.

(2) WL Dahut et al, Randomized Phase III Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer, J. Clinical Oncology, Vol 22, No. 13, July 1, 2004, pp. 2532-2539.

Table 11. Taxol (paclitaxel) and carboplatin and with or without Estramustine Phosphate(Emcyt).

Reference Phase and No. of patients Taxol Carboplatin Emcyt Overall RR Complete RR Median OS

(1) A. Meluch et al, ASCO 2004, abstract 4659. (a)
II, 86 Q weekly (90mg/m² IV days 1, 8, 15) 3 of 4 weeks.
Arm A (N=39) weekly (AUC 2, days 1, 8, 15)

140mg PO TID days 1-3, 8-10, 15-17.
Arm A

61%

10% Arm A, 20.3 mos.

Arm B(N=42):q 4 weeks, day 1, AUC 6 Arm B, 50% 10% 15.9 mos.

PSA RR MD-RR MTP or MS

(2) WK Kelly, et al, J Clin Oncol. 2001 Jan 1;19(1):44-53.”TEC”

Chemo-naïve.

(b)

I, 8; II, 48

Q weekly, 100 mg/m2
AUC 6, day 1 of 4 week cycle. oral estramustine (10 mg/kg), max 840mg/day. Days -2 to +2. 67% (42/54)
45%

15/33

MTP 21 weeks (range 1-123 wks.) MS 19.9 mos.

a. The authors also list the Median PFS 10.1 mo for Arm A and 9.7 mo for Arm B. The Median OS 20.3 mos for Arm A vs 15.9 mos for Arm B.

b. This study had 12 patients with DVTs and 2 pulmonary embolisms (25% of the patients.) Patients then rec’d anticoagulation. Extend of disease: 23 bone metastases only; 8 soft tissue metastases only and 25 both bone and soft tissue metastases.

(1) A Meluch, F. A. Greco, H. A. Burris, J. B. Erland, R. A. Khan, G. I. Rodriguez, J. G. Gandhi, J. D. Hainsworth; Weekly paclitaxel/estramustine phosphate plus carboplatin administered either weekly or every 4 weeks in the treatment of hormone refractory prostate cancer (HRPC): A randomized phase II trial of the Minnie Pearl Cancer Research Network. ASCO 2004, Abstract 4659.

(2) Kelly WK, Curley T, Slovin S, Heller G, McCaffrey J, Bajorin D, Ciolino A, Regan K, Schwartz M, Kantoff P, George D, Oh W, Smith M, Kaufman D, Small EJ, Schwartz L, Larson S, Tong W, Scher H., Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.
J Clin Oncol. 2001 Jan 1;19(1):44-53.

Table 12. Mitoxantrone(Novantrone) with or without Ketoconazole and with or without Estramustine Phosphate (Emcyt).

Reference Phase and No. of Patients Mitoxantrone Ketoconazole Emcyt
PSA-RR

> 50%
M-RR MTP or MS

(1)Tannock et al, NEJM 2004. III, 300 12mg/m2, q 3 weeks plus prednisone 5mg BID qd - - 32% of 300 with 7.8 mos median duration. 7% of 137 patients. MDS 16.5 mos. (this was 10-12.5 in previous CALGB studies and was 21 mos in a study with asymptomatic patients.

(2)Petrylak et al, NEJM 2004. III, 384 12 mg/m2, q3 weeks plus prednisone 5mg BID qd - - 27%(82 of 303 patients 11% PR (10 of 93) MS 15.6 mos and MTP 3.2 mos.

(3)GF Samelis et al, Urology 2003. (a), (b) II, 26 20 mg total dose - 140mg TID continuously. 13 (50%) and 8 of these had PSA declines of more than 80%. 27%(CR+PR), 7 patients had disease stabilization MDR 9 mos (8-25 mos); MD of disease stabilization 6 mos and MTP 7 mos (3-20+ mos). MS 15 mos (4-31+ mos).

(4) M Kozloff et al; ASCO 2002; Abstract No: 778 (a) phase II, 23 12mg/m2 q 3 weeks. continuous ketoconazole 400 mg po TID (given with ascorbic acid 250 mg po TID) - 16 (73%), but they also list 2 (9%) as having a complete remission for a total of 82% - -

(a) If high dose pulsed calcitriol (.5mcg/kg) were added to this tx, one might improve the RR if high dose calcitriol were synergistic with mitoxantrone.

(b) the metastatic sites were 4 only osseous, 10 only measurable disease; 8 osseous and metastatic organs; 4 with more than 2 metastatic organs and 1 with rising PSA only. Sites were bones (12), Nodes (10), Local recurrence (8), Liver (6), Lung(6) and other (1 - pleuritic fluid).

The 1st two references are from phase III trials comparing taxotere with mitoxantrone. There are several previous phase III trials comparing mitoxantrone/pednisone with prednisone alone (or hydrocortisone instead of prednisone). These are not included here.

(3) GF Samelis, et al, The Combination of Estramustine and Mitoxanrone in Hormone-Refractory Prostate Cancer: A phase II Feasibility Study Conducted by the Hellenic Cooperative Oncology Group, Urology 61: 1211-1215, 2003.

(4) Mark Kozloff, Joy Vlamakis, Eryn Ferdman, Margarett Mariott, Lilia Gallot, Borko Jovanovic, Lawrence Schilder, Raymond C Bergan, Phase II trial of mitoxantrone and ketoconazole for hormone refractory prostate cancer, ASCO 2002; Abstract No: 778. This trial was an attempt to have a less toxic combination than adriamycin plus ketoconazole -- which had a high response rate, but also had high toxicity.

Author: Howard Hansen 2/5/2005. Last update: 1 March 2010

While every effort has been made to make these tables accurate, it is best to refer back to the references for verification and additional information.

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