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Chemotherapy Combination Promising for Advanced Prostate Cancer

Taxotere and Emcyt Phase II Report

New York, May 7, 2001 (PSA Rising) -- Combination chemotherapy using docetaxel (Taxotere®) and estramustine phosphate (Emcyt®) plus low-dose hydrocortisone is an effective and "moderately well tolerated" treatment for men with advanced prostate cancer. The final report on a Phase II trial done by the Cancer and Leukemia Group B (CALGB) was published May 1 in Journal of Clinical Oncology.

For advanced prostate cancer, chemotherapy has become a more promising treatment since the discovery of the taxane drugs -- Taxol, derived from the Pacific yew tree, and docetaxel, a synthetic compound.

"Options for patients with advanced disease, once limited to the use androgen deprivation," says Dr. Eric Small of UCSF, "have expanded to include a number of interventions, including secondary hormonal manipulations, chemotherapy, and a variety of investigational approaches."

Hormone-refractory prostate cancer refers to advanced disease in which a substantial population of cancer cells resists first- and second-line hormonal blockade drugs like Lupron or Zoladex and Casodex or Flutamide.

Several clinical research studies of chemotherapy have been done for advanced androgen-independent prostate cancer in the the last ten years. At the start it looked as though chemotherapy would not extend patients' survival, but this may be changing.

"This is the first multicenter trial," said lead investigator Diane Savarese, MD, Associate Professor of Medicine, University of Massachusetts Memorial Medical Center in Worcester, "to show that the combination of docetaxel, estramustine and low-dose hydrocortisone is an effective and tolerable regimen for hormone-refractory prostate cancer, with response rates higher than those reported for other estramustine combination regimens." Earlier trials conducted at single medical centers included Dr. Daniel Petrylak's 1999 trial at Columbia University, Columbia Presbyterian Medical Center.

"Our findings," Savarese said, "support an enhanced role for chemotherapy in the management of hormone-refractory prostate cancer, and the data suggest that the docetaxel/estramustine combination may represent a new treatment approach."

The study included 47 men with very advanced disease (performance status of 0 to 2 on a scale of 10) whose prostate cancer had progressed after initial hormone therapy. Patients were not eligible if they had already taken chemotherapy, had a history of thrombotic events or severe cardiovascular disease, or had active thrombophlebitis.

Emcyt has a tendency to cause blood clots --nine percent of these patients developed a blood clot (or thromboembolic event). Outside of a trial, patients might be allowed to take a blood thinner upfront. This trial also excluded patients with clinically significant neuropathy. Neuropathy (loss of sensation in hands and/or feet) is common during extended treatment with docetaxol and most other chemotherapy drugs. Folic acid is reputed to be somewhat helpful for neuropathy, and drugs to overcome it are in the pipeline.

Doses on three week cycle - and results

Men in the CALGB study received intravenous docetaxel, 70 mg/m2 (70 mg per meter of body height squared) on the second day of every three-week cycle. They took oral estramustine, 10 mg/kg/day in divided doses for five days every three weeks. Oral low-dose hydrocortisone, 40 mg/day, they took in divided doses -- 30 mg in the morning and 10 mg in the evening. And they also took oral dexamethasone, 8 mg twice a day on days one to three of each therapy cycle.

Overall, 46 patients were evaluable for response and/or toxicity. Of the 44 men with initially elevated PSA (prostate-specific antigen) levels, 30 (68 percent) had a 50 percent or greater decline in PSA and 25 (57 percent) had a 75 percent or greater decline.

Twenty-four of 46 patients had measurable soft tissue disease. Three of these patients had a complete response, and nine patients had a partial response in soft tissue, for a measurable disease response rate of 50 percent. A complete response was defined as a complete disappearance of all clinical and X-ray signs of cancer with normalization of serum PSA, while a partial response referred to a 50 percent or greater decrease in measurable tumor size and a 75 percent or greater reduction of PSA with a stable or improved PSA. With a median follow-up of 16 months, the median survival was 20 months. In 1999, Dr. Daniel Petrylak at Columbia University, Columbia Presbyterian Medical Center, reported median survival of 22 months.

Side effects

The commonest side effect of the treatment was neutropenia (low white blood cells -- so, vulnerability to infections), with 26 percent of patients developing grade 3 granulocytopenia (lowering of granulocyte, or type of white blood cells) and 30 percent of patients having grade 4 granulocytopenia. Outside of a trial, this condition can be prevented or lessened by use of supportive medications, notably neupogen.

Other common side effects were edema (puffiness and swelling) in 22 percent of patients, shortness of breath (dyspnea) in 22 percent of patients, and malaise and/or fatigue in 24 percent of patients, and hyperglycemia.

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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.

A Phase III trial is underway to compare the regimen of docetaxel and estramustine to the combination of mitoxantrone and prednisone for patients with hormone-refractory prostate cancer, Dr. Savarese said. In the USA docetaxel and estramustine are available for prostate cancer outside of trials through "off-label" use.

Dexamethasone is used with taxotere to reduce fluid retention. But it has side effects of its own. Dr. Petrylak's team ran a small test to see if dexamethasone plays any active part in shrinking the cancer. Dexamethasone and other steroids improve feelings of well-being and may reduce pain, and have been viewed as a poor man's anti-androgen -- able to block a hormone that stimulates adrenal androgens. But steroids may worsen osteoporosis or other bone damage associated with hormonal blockade.

Prostate cancer cells become refractory to steroids such as HDC, prednisone and/or dexamethasone. Dr. Petrylak found that dexamethasone "does not significantly contribute to the PSA response rate of estramustine and docetaxel" (Petrylak, D., Katz A. 1999).

Links, Related Studies and Future Developments

Excerpt from
Dancing with Doctors

by Ric Masten
April 4, 2001 The chemo last Monday was my 5th weekly session. The first two went without incident. Before they drip the chemo they give me 10mg Decadron (a steroid) to minimize the possible negative reactions to the Taxotere. And man, does the steroid jack me up ... the Decadron has me shaking my wife awake at midnight shouting, "Let's go dancing!!!" First two sessions took an hour to infuse the Taxotere. On the third session they speeded the process up to 30 minutes. And I had a Taxotere extravasation -- chemo spill. The vein broke and the Taxotere went out into the tissue around the needle. All of a sudden I felt something akin to a bee sting. Looked down at the back of my hand there was a "bleb" small bulge at the needle site. I rang for the nurse -- but she was busy with another patient so another three minutes passed before she got to me and turned the drip off and moved the IV to the other hand and we finished the session. But I had about 6 minutes of Taxotere spilling out into the tissue on the back of my left hand. No one seemed concerned about the incident -- or told me to watch for trouble or that I might have a problem....
Wound from chemo, photo

Taxotere/Emcyt - One Man's Story
Dave Kressen's history of Prostate Cancer treatments updated 10/11/98, at Don Cooley's Cooleyville.

Taxotere (Aventis) and Emcyt (Drug information)

J 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.

Docetaxel (Taxotere) in hormone-refractory prostate cancer. Petrylak DP. [Daniel Petrylak] Division of Medical Oncology, College of Physicians and Surgeons of Columbia University, Columbia Presbyterian Medical Center, New York, NY 10032-3789.

Hormone-refractory prostate cancer: an evolving standard of care. Small EJ, Reese DM, Vogelzang NJ. University of California, San Francisco Comprehensive Cancer Center, 94115, USA.Semin Oncol 1999 Oct;26(5 Suppl 17):61-7

Triangle Urological Group, 1999 found "substantial single-agent activity of docetaxel in hormone refractory prostate cancer."

Petrylak, D., Katz A. 1999 found steroid did not improve PSA result.

Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study. Williams JF, Pienta KJ, et al. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor 48109-9480. Prostate 2000 Sep 1;44(4):275-8 "These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone."

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.

Cancer and Leukemia Group B (CALGB) is a national clinical research group supported largely by money from the NCI to develop improved treatments for cancer. Headquartered at the University of Chicago, CALGB represents a national network of 29 university medical centers, over 185 community hospitals and 3,000 physicians. CALGB research covers seven major disease areas: leukemia, lymphoma, breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer and melanoma. Nationally known experts coordinate the treatment programs to help improve cure rates.
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