Prostate Cancer: Chemotherapy (Written Primarily For The Medical Oncologist)

Contiued from PROSTATE CANCER: CHEMOTHERAPY

Taxotere

Emcyt has also been combined with Taxotere (docetaxel). Taxotere is most often administered as an every-3-week regimen. The recent work of Natale using weekly Taxotere has led us to employ this patient-friendly regimen. Presented are the data from the work of Petrylak et al. on every 3-week Taxotere and that of Natale et al. using weekly Taxotere.

Taxotere + Emcyt

Emcyt 280 mg 3x/day x 5 days + Taxotere @ 40-70 mg/m² every 21 days. Decadron pretreatment to prevent side-effects
Extensive Pretreated Pts 50% with > 50% decline in PSA
Minimally Pretreated Pts 73% with > 50% decline in PSA
53% reduced pain meds by > 50%

Petrylak: Proc Am Soc Clin Oncol. 16:310A, 1997

Taxotere is synergistic with Cytoxan, 5-FU, and Mitomycin C. There is virtually no bone marrow suppression using weekly Taxotere at the dose we employ (25 mg/m2/week). We also are finding this regimen to have minimal, if any, tendency to cause nausea or vomiting and to cause only slight hair thinning (which is reversible). Taxotere's mechanism of action may involve inactivation of BCL-2 via phosphorylation. Since 65% of AIPC specimens overexpress Bcl-2 (which inhibits apoptosis), this may be a critical area of Taxtotere action. In vitro, Taxotere has 100-fold greater potency than Taxol in inactivating Bcl-2 phosphorylation.

1999 Update Weekly Taxotere + Emcyt
(Natalie et al)

50% PSA Drop 14/18 (77.7%)
75% PSA Drop 9/18 (50%)
Objective Response 4/6 (66.7%)
Improved Sx Control or KPS 12/14 (85.7%)

5-FU + Interferon a-2a

5-FU-by continuous infusion given in combination with subcutaneously administered Interferon- alpha-resulted in a 43% response rate with a median survival time of 18 months. This is shown here.

5 FU + Interferon-a-2a

5 FU by continuous infusion @ 600 mg/m² per day x 5 days followed by bolus injection 5 FU on days 15,22.
rIFN- -2a 3x10⁶ on days 1,3,5,15,22
Repeat cycle every 4 weeks
59/21 (43%) with PSA response >50%
Median survival 18 months

Shinohara N, Demura T, Matsumura K et al. The Prostate 35:56-62, 1998

Mitoxantrone + Prednisone

The study of Tannock et al. indicated a median survival time of 12 months with or without the addition of prednisone. Patients receiving Mitoxantrone and Adriamycin need to have baseline ejection fractions done and interval ejection fractions to prevent the development of significant cardiomyopathy. The use of coenzyme Q10, selenium, and vitamin E in such patients may have some protective value. The data from the two major Mitoxantrone studies are shown below. There are many investigational trials using Mitoxantrone combinations.

Mitoxantrone (M) + Prednisone (P)

M @ 12mg/m² every 3 weeks + P 10 mg per day vs P alone
Reduction in pain & analgesic use
38% response in M+P vs 21% with P alone
> or = 50% in PSA in 33% MP vs 22% P Duration of response 43 wks vs 18 wks
Median survival 12 months: no difference

Tannock I, Osoba D, et al: JCO 14:1756-64, 1996.

Mitoxantrone (M) + Hydrocortisone (HC)
vs HC only

101 patients with AIPC received either M + HC or HC alone. 50% decline in PSA seen in 33% of M + HC arm and 18% in HC only arm (p 0.035)
Time to failure 7.3 m in M + HC arm and 4 m in HC only (p value 0.065)
Survival 10.9 m vs 11.8 m (p 0.329)

Kantoff PW, Conaway M, Winer E, et al. Proc Amer Soc Clin Oncol 15:25a, 1996.

The above regimens are used to treat adenocarcinoma of the prostate. Two regimens that we have used successfully to treat small-cell prostate cancer (SCPC) are shown below. SCPC is characterized by elevations in neuroendocrine markers such as CGA, NSE, and, not uncommonly, CEA. The PSA may not be expressed significantly, bone lesions are often lytic and not blastic, and liver and lung lesions are not uncommonly detected by CT scanning.

Small Cell PC Regimens

CDE
Cytoxan 50 mg bid x 14 days
Doxorubicin (adriamycin) 20 mg q wk
Etoposide (VP-16) 50 mg qd x 14-21 days
Neupogen support essential, Epo also

Small Cell PC Regimen

Adriamycin + Cytoxan
Infusion Adriamycin plus Cytoxan over 96 hrs
Using Port-A-Cath
Adriamycin at 10 mg/m² per day + Cytoxan t 200 mg/m² per day
Cycle repeated every 22 days
>Neupogen used from days 5-10 at 600 ug qd
Dose escalation of Cytoxan pending CBC

Small Cell Clinical Vignette

77 yo with PC 7/91
Failed RP, ADT
CDE 4/93: baseline NSE 119
Response x 2 years, then infusion CDE 9/95 & response x 1 yr
relapse 12/96 with rise in CGA to 99
Infusion Cytoxan and Adria 3/97 with response to 9/97

Conclusions

The chemotherapy of PC has changed significantly in the last 5 years. We are defining AIPC more precisely, detecting AIPC earlier, and treating patients at a lower tumor burden when the chance of a significant response is still possible. There remains, however, a need to educate patients and physicians about these and other fundamental issues in the care of the patient with AIPC. The coming years will see combinations of synergistic drugs, the employment of agents that affect angiogenesis, oncogenes, and growth factors as ways to eradicate the tumor cell population. The ability to control PC may be within our reach.

Further Information

Chemotherapy Options for Advanced Prostate Cancer

By Mark A. Moyad, M.P.H., and Kenneth J. Pienta, M.D., University of Michigan Comprehensive Cancer Center

Note: All of this information and in more detail is found in the upcoming book The ABCs of Advanced Prostate Cancer (Sleeping Bear Press, (800) 487-2323). The percentages that are shown are the percent of individuals who respond or who are affected by the treatment.

The National Comprehensive Cancer Center
Endorsed Chemotherapies

Drugs	PSA response	Side effects
Estramustine and Etoposide	39-58%	Nausea (decreases with decreasing estramustine dose), hair loss, decrease in white blood cells (about 25%), and blockage of the veins in the legs (less than 5%).
Paclitaxel (Taxol) and Extramustine	53%	Nausea, breast enlargement, fluid buildup, and a decrease in white blood cells (21%).
Ketoconazule and Doxorubicin (Adriamycin) Is also given with hydrocortisone	55%	Remote possibility of sudden cardiac death-two patients have died-and inflammation of some areas of the body.
Mitroxantrone and Prednisone	33%	A mild case of nausea.
Estramustine and Vinblastine	54-61%	Nausea (20%), decrease in white blood cells (12%), constipation (20%), and temporary neuropathy (12%).

Newer Combinations and Options

Drugs	PSA response	Side effects
Paclitaxel, Extramustine, and Etoposide	53%	Nausea, hair loss, fatigue, and a decrease in one type of white blood cell
Doxorubicin/Ketoconazole alternating with Vinblastine/Estramustine Is also used with hydrocortisone	67%	Swelling or edema (49%), blockage of the veins in the legs (18%), cardiac problems (4%), and a decrease in one type of white blood cell (less than 2%)
Cytoxan, Diethylstilbestrol (DES), and Prednisone	39%	Minimal

Secondary Hormonal Therapy
(Newer Options)

Drugs	PSA response	Side effects
Low-dose DES	43%	Nipple sensitivity (90%), blockage of the veins in the legs (5%), and breast enlargement (14%)
High-dose Casodex	23%	Hot flashes (40%), nipple sensitivity (5%), nausea (10%), itching (5%), and breast enlargement (5%)

For referrals to doctors experienced in using combined hormone blockade, cryo-ablation therapy, seed implantation, etc., call The Educational Center for Prostate Patients at (516) 997-1777 or PAACT at (616) 453-1477, or access the Web site of the Prostate Cancer Research Institute [http://www.prostate-cancer.org.]. Hytrin, Cardura, Lupron, Zoladex, Casodex, and Eulexin are drugs that can be prescribed by your doctor.

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