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


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).


CONCLUSIONS
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.
Figg
William D
WD
Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, Cancer Therapy and Evaluation Program, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, MD 20892, USA. wdfigg@helix.nih.gov
Li
Haiqing
H
Sissung
Tristan
T
Retter
Avi
A
Wu
Shenhong
S
Gulley
James L
JL
Arlen
Phil
P
Wright
John J
JJ
Parnes
Howard
H
Fedenko
Kathy
K
Latham
Lea
L
Steinberg
Seth M
SM
Jones
Elizabeth
E
Chen
Clara
C
Dahut
William
W
D000368:Aged; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000077143:Docetaxel; D004961:Estramustine / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage; D016896:Treatment Outcome
D000728:Androgens; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D013792:Thalidomide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1