New treatment approach
for recurrent prostate cancer
After Failed Prostatectomy or Radiation,
Chemotherapy Then Hormonal Blockade

June 13, 2001 (PSA Rising). Recurrence of prostate cancer after radical surgery or external beam radiotherapy confronts patients with hard choices. A PSA rise may show up months or years before a positive bone scan or any symptoms. The velocity of biochemical relapse -- marked by rising prostate specific antigen -- varies according to the patient's risk.

"The population of men with prostate cancer who have a rising PSA without clinically apparent metastasis after local therapy, known as Stage D0 prostate cancer, is ever increasing," said Mary-Ellen Taplin, M.D., Associate Professor of Medicine at the University of Massachusetts Medical School.

Despite increase in early detection and treatments aimed at cure -- surgery, external beam radiation or seed implants with or without external radiation -- three out of ten men treated experience recurrence.

For patients with prostate cancer that has come roaring back in the form of early biochemical recurrence of high-grade disease (Gleason 8-10) with rapid PSA doubling time, Dr. Taplin's group in Massachusetts and another team in Maryland are testing a new approach. Patients take a chemotherapy combination, docetaxel (Taxotere®) and estramustine (Emcyt®), before they go on any hormonal blockade.

"While the optimal therapy for these patients has not been established," Dr. Taplin says, "our findings indicate that combining docetaxel and estramustine with short term androgen withdrawal is a promising treatment strategy that should be explored in larger trials."

Arif Hussain, M.D., a prostate cancer specialist at the University of Maryland Greenebaum Cancer Center, is also reversing the order of treatment for men with early recurrent prostate cancer by giving them chemotherapy first, followed by hormone therapy. "Traditionally, chemotherapy is not used for this group of patients," Dr. Hussain says. "It is often reserved for men who have advanced, metastatic prostate cancer, following hormonal therapy. Unfortunately, most advanced prostate cancers develop resistance to traditional therapies over time," says Dr. Hussain. "By using chemotherapy first in patients with early, recurrent disease, we may be able to more effectively kill prostate cancer cells before they develop resistance, and that is the rationale behind this new approach."

The idea of upfront chemotherapy for prostate cancer is to kill off cells that will not respond at any time to hormonal therapy -- hormone-insensitive prostate cancer cells. Hormonal blockade can only knock out cells that depend on hormones; if even a few cancer cells are able to survive without this fuel, as other cells die off they gain space to increase their population, mutate and become more resistant to any future therapy.

Dr. Hussain's ongoing, phase II study has evaluated 26 patients so far. Patients who completed chemotherapy before starting hormonal therapy showed a 57 percent decline in their PSA levels. "All of the patients treated with chemotherapy went on to respond to the hormone therapy, and we believe that such a combination could possibly be more effective in controlling recurrent prostate cancer," says Dr. Hussain.

Docetaxel is FDA approved to treat lung and breast cancer. Docetaxel and estramustine combination is entering Phase III trials for advanced prostate cancer. And some oncologists are trying docetaxel -estramustine or other chemotherapy right upfront, ahead of surgery and/or radiation, for early-stage aggressive disease in newly-diagnosed men.

For patients with biochemically recurrent disease, Dr. Taplin says, docetaxel and estramustine combination therapy "results in rapid normalization of PSA and is generally well tolerated. " How far the PSA drop is "cytotoxic" (reflects death of cancer cells) compared to how far it comes from "hormonal effects" is as yet "unclear," she says. Nor do the researchers know how long complete responses will last. The patients will continue to be tracked after they come off hormonal blockade.

In Dr. Taplin's study, 15 men have been followed so far. The median Gleason score is above 8 and PSADT less than 4 months. They had rising PSA's but no apparent sign of local failure or metastases.

MEDICATION SCHEDULE

• Estramustine 10 mg/kg/d divided into three daily doses on days one to five, orally on an empty stomach.
  
  
• Docetaxel 70 mg/m2 intravenously over one hour on day two every 21 days for four treatment cycles.
  
  
• Premedication with dexamethasone 8 mg administered orally twice daily 24 hours before, and 48 hours after, the docetaxel.
  
  
• Hormonal therapy began on week 13 --antiandrogen bicalutamide (Casodex) 50 mg orally per day, LHRH agonist goserelin (Zoladex) 10.8 mg injected subcutaneously every 12 weeks for a total of 15 months.
  
  
• The Maryland protocol (Dr. Hussain's) calls for 4 mos of total androgen suppression (TAS; LHRH agonist + Bicalutamide 50mg/d), and then 8 mos of peripheral androgen blockade (PAB; Finasteride (Proscar) 5mg/d + bicalutamide 50mg/d).

All 15 Massachusetts's patients have completed four cycles of chemotherapy. After two cycles, eight of the 15 men or 53 percent had achieved a complete response, defined as normalization of the PSA level (undetectable for RP, below 4ng/dl for EBRT). At completion of four cycles, 12 of the 15 patients, or 80 percent, had a complete response.

Side effects were about the same as in other recent studies of docetaxel and estramustine for prostate cancer, Dr. Taplin says. Grade 3-4 neutropenia (low white blood cells, which can make the patient susceptible to infection) was seen in 53 percent of patients; but no infections were recorded. Dr. Hussain reports Grade 4 neutropenia in 10 patients, Grade 3 infection in 1, Grade 3 transaminitis in 1, Grade 3 pancreatitis in 1.

Both docetaxel (Taxotere®) and estramustine (Emcyt®) are associated with increased risk of blood clots. Initially, neither of these trials offered patients blood thinners. This is not unusual -- warfarin (Coumadin) adds some risk of bleeding. It was not given in a related Phase II study of docetaxel and estramustine in men with hormone-refractory prostate cancer; there, 9% of patients had thromboembolic events during therapy. In this ongoing trial for men with biochemical recurrence, one of Dr. Taplin's 15 patients suffered "a minor mini-stroke," the ASCO abstract records, and another developed deep vein thrombosis. The doctors began routine use of prophylactic warfarin (1 mg/day).

Docetaxel and Emcyt combination "results in rapid normalization of PSA and is generally well tolerated," Dr. Taplin says. How far the PSA drop is cytotoxic (i.e. reflects death of cancer cells) and how far hormonal effects are responsible is "unclear," as yet, the doctors say. How long complete responses will last (durability of response) will be tracked after the patients come off Zoladex.

If you want more information about Dr. Mary-Ellen Taplin's ongoing study, read the outline at ClinicalTrials.gov or call (508)856-3550. Results so far were reported at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO).

You can visit University of Maryland Medical Center online at http://www.umm.edu/

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LINKS

1. Abstracts from ASCO, May 2001
Docetaxel (D), Estramustine (E) and Short Term Androgen Withdrawal for Patients with a Rising PSA After Definitive Local Treatment of Prostate Carcinoma. Daniel E Morganstern, Mary-Ellen Taplin, Glenn J Bubley, Lahey Clinic, Burlington, MA; University of Massachusetts Memorial Medical Center, Worcester, MA; Beth Israel Deaconess Medical Center, Boston, MA.

Docetaxel Followed by Hormone Therapy in Men Who Fail Biochemically After Definitive Local Treatments for Prostate Cancer. A. Hussain, N. Dawson, P. Amin, M. Naslund, S. Dibiase, C. Engstrom, S. Swallow, B. Dorsey, T. Chen, L. Holder, B. Line, University of Maryland, Baltimore, MD

2. PSADT: PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H. Department of Urology, Mayo Clinic, Rochester, Minn 55905, USA. Mayo Clin Proc. 2001 Jun;76(6):576-81. (Gives an indication of how to judge which R-P patients with recurrence may most need immediate therapy).

3. The drugs: Taxotere (Aventis) and Emcyt (Drug information).

Taxotere® (docetaxel) full prescribing information

Potential Side Effects During Taxotere Administration and Management of Side Effects (Aventis). Note: this is about side effects of use of Taxotere for breast cancer, for which standard dose is 100 mg/M2 (i.e. per meter of patient's height squared). For prostate cancer the typical dose is lower (as above, 70 mg/M2) and side effects may be a bit milder.

Clin Oncol 2001 May 1;19(9):2509-16 Phase ii study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of calgb 9780. Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, Hussain A, Small EJ, Vogelzang NJ. University of Massachusetts Memorial Health Care, Worcester, and Boston Medical Center, Boston, MA. (similar regimen for hormone-refractory PCa)

Semin Oncol 1999 Oct;26(5 Suppl 17):14-8 Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Picus J, Schultz M. Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

Emcyt requires care with diet. Swedish researchers found in 1990 that it should not be taken together with milk, milk products or other calcium-rich food or drugs. Emcyt can cause some upset stomach, but severe gastrointestinal disturbances were infrequent, the CALGB researchers said. Prescription strength or over the counter meds like Pepcid usually handle this.

Sweden, 1990 -- "the rate and extent of absorption of estramustine phosphate were decreased when the drug was taken with milk or food due to the formation of a poorly absorbable calcium complex. To obtain high and reproducible absorption ... the drug should not be taken together with milk, milk products or other calcium-rich food or drugs."

Calydon CV787, now in PhaseI/II human clinical trials, in lab tests on mice with prostate cancer shows some promise as an enhancer of taxotere and taxol. Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Yu DC, et al., Cancer Res 2001 Jan 15;61(2):517-25.