Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens.
BACKGROUND
Physicians typically switch therapies unless clinically relevant thresholds of response are observed, and treatments that produce high-quality responses and that are active in the salvage setting are generally felt to be promising. With the goal of efficiently selecting promising regimens for more advanced trials, we conducted a randomized selection trial of four regimens to identify promising treatments for androgen-independent prostate cancer.


METHODS
Patients without prior exposure to cytotoxic therapy were randomly assigned to one of four regimens (i.e., cyclophosphamide, vincristine, and dexamethasone [CVD]; ketoconazole plus doxorubicin alternating with vinblastine plus estramustine [KA/VE]; weekly paclitaxel, estramustine, and carboplatin [TEC]; paclitaxel, estramustine, and etoposide [TEE]). Patients were evaluated every 8 weeks to assess response and adverse events. Patients who responded continued with the same treatment; those who did not were randomly assigned to one of the other three treatments. Response was assessed by considering tumor-specific symptoms, tumor regression, and prostate-specific antigen (PSA) changes. Treatment was continued until two consecutive courses induced a response (i.e., overall success, the major criterion for which was 80% PSA reduction) or until patients were given two different regimens that failed to induce such a response.


RESULTS
Median overall survival from registration among all 150 patients was 22 months (95% confidence interval [CI] = 19 to 26 months). Estimated survival at 3 and 5 years, respectively, was 26% (95% CI = 20% to 35%) and 10% (95% CI = 5% to 16%). Overall success was achieved in 35 patients with the initial treatment (i.e., four treated with CVD, seven with KA/VE, 14 with TEC, and 10 with TEE) and in nine more patients with a second-line regimen (i.e., two with CVD, five with KA/VE, and two with TEC). For all 44 (29%, 95% CI = 23% to 37%) patients with overall success, median survival was 30 months (95% CI = 26 to 40 months); for the other 106 patients, it was 19 months (95% CI = 17 to 22 months). TEC produced the greatest number and proportion of successful courses of treatment, and TEC followed by KA/VE was the most promising two-stage strategy.


CONCLUSIONS
Some patients responded to particular treatments, and responses to second-line treatments were not rare. We propose that TEC be considered for phase III evaluation.
Thall
Peter F
PF
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Logothetis
Christopher
C
Pagliaro
Lance C
LC
Wen
Sijin
S
Brown
Melissa A
MA
Williams
Dallas
D
Millikan
Randall E
RE
D000368:Aged; D000465:Algorithms; D000728:Androgens / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004961:Estramustine; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D012107:Research Design; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage; D014750:Vincristine / Q000008:administration & dosage
D000728:Androgens; D004961:Estramustine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D016190:Carboplatin; D017430:Prostate-Specific Antigen; D017239:Paclitaxel; D007654:Ketoconazole