Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer.

Abstract

OBJECTIVE:

To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC.

PATIENTS, MATERIALS AND METHODS:

In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days.

RESULTS:

In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013).

CONCLUSION:

Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.

• Authors: William D Figg, Haiqing Li, Tristan Sissung, Avi Retter, Shenhong Wu, James L Gulley, Phil Arlen, John J Wright, Howard Parnes, Kathy Fedenko, Lea Latham, Seth M Steinberg, Elizabeth Jones, Clara Chen, William Dahut
• Journal: BJU international (BJU Int) Vol. 99 Issue 5 Pg. 1047-55 (May 2007) ISSN: 1464-4096 [Print] England
• PMID: 17437439 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Androgens
• Taxoids
• Docetaxel
• Estramustine
• Thalidomide
• Cytochrome P-450 Enzyme System
• Aryl Hydrocarbon Hydroxylases
• CYP1B1 protein, human
• Cyp1b1 protein, mouse
• Cytochrome P-450 CYP1B1

Topics

• Aged
• Androgens (metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Aryl Hydrocarbon Hydroxylases
• Cytochrome P-450 CYP1B1
• Cytochrome P-450 Enzyme System (genetics)
• Docetaxel
• Estramustine (administration & dosage)
• Genotype
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• Prostatic Neoplasms (drug therapy, genetics, mortality)
• Survival Analysis
• Taxoids (administration & dosage)
• Thalidomide (administration & dosage)
• Treatment Outcome