Early Androgen Ablation Research Articles

Serum proteomics and ingenuity pathway analysis (IPA)-guided discovery of response markers to androgen ablation (AA) in prostate cancer.

11 Background: Currently there are no serum markers of response to AA. We performed a proteome based analysis of serum from prostate cancer patients, followed by mapping of candidate markers to networks based on known molecular interactions in Ingenuity Knowledge Base (IKB). Methods: Isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) was performed in serum of 3 non-localized prostate cancer cohorts. The first cohort included 15 paired untreated hormone-sensitive “pre AA” and 3-month “post AA” specimens; the second included 10 “early AA failure” (median failure time: 11 months) and the third included 10 “late AA failure” specimens (median failure time: 95 months). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post AA proteomes and (ii) post AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. To facilitate biological interpretation of multiple candidates identified in the comparisons, IPA was used. Candidate markers implicated in IPA networks with statistical significance were pursued in a second, independent patient cohort for association with time to AA failure using univariate Cox regression analysis. Results: Median PSA for pre/post AA first cohort were 3.15 and 0.29 ng/ml. Median PSA for the second and third cohorts were 27.3 and 4.3 ng/ml. Between post AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. Network enrichment analysis of the 47 proteins by IPA identified four interaction networks (p<0.01), one of which highlighted a role for 17-β-estradiol (E1). Gas chromatography used for measuring 3-month post AA initiation serum E1, estrone (E2) and testosterone levels (N=38) detected high E1, E2 levels associated with longer time to AA failure (P=0.07 for E1; P=0.08 for E2) in the independent cohort. Conclusions: A global proteomic analysis identified post AA initiation serum E1, E2 levels as potential response markers, which needs validation.

Serum proteomics guided discovery of predictive biomarkers of response to androgen ablation (AA) in prostate cancer.

104 Background: Currently there are no serum predictive markers of response to AA. We used a proteomic based analytic approach to identify candidates. Methods: Serum from three non-localized prostate cancer cohorts was analyzed. The first included15 paired untreated hormone-sensitive “pre-AA” and 3-month “post-AA” specimens; the second included 10 “early AA failure” (median time to AA failure:11 months) and the third included 10 “late AA failure” specimens (median time to AA failure: 95 months). Proteomic analysis was performed with isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post-AA proteomes and (ii) post-AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. ELISA assays were used to verify candidate markers in a second stored aliquot of first cohort specimens. This cohort was followed for AA failure. Association of post-AA ELISA levels of candidate markers with time to AA failure was performed using Cox proportional hazards regression, summarized as relative risk (RR) for AA failure. Results: Median PSA in pre/post-AA first cohort were 3.15 ng/ml and 0.29 ng/ml. Median PSA in the second and third cohorts were 27.3 and 4.3 ng/ml. Between post-AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. ELISA assays verified expression levels of 2/47 proteins in the first cohort; zinc alpha-2 macroglobulin (ZAG), and Neuropilin-2 (NPL2). Median change in ZAG decreased by 2073.5 ng/ml (post versus pre-AA) while median change in NPL2 levels increased by 2.9 ng/ml. After a median follow-up of 43 months from the post-AA time-point, 4/15 first cohort subjects had failed AA. The RR of AA failure for ZAG levels below the median change was 3.8 (95% CI: 0.4-37) and 3.0 (95% CI: 0.3-29) for NPL2. Conclusions: A global proteomic analysis identified ZAG and NPL2 as candidate serum predictive markers of AA response which needs further validation.

Survival benefit for early hormone ablation in biochemically recurrent prostate cancer

Purpose To determine whether early initiation of androgen ablation in patients with biochemically recurrent prostate cancer, but without clinically evident metastases, is associated with improved overall or disease-specific survival. To describe subgroups, based on PSA kinetics, which are most likely to benefit from early androgen ablation. Materials and Methods A retrospective cohort of 124 patients, who were definitively treated by external beam radiotherapy between 1988 and 1999, and subsequently received androgen ablation for biochemical (92 patients) or clinically metastatic (32 patients) failure, was reviewed. Median follow-up time was 6.2 years. Overall survival, disease-specific survival, and hormonal control were examined and compared for patients whose hormone ablation was started early (prostate-specific antigen [PSA] ≤15 ng/ml or PSA doubling time >7 months) or late in the course of their biochemical failure. Results All patients had biochemical response to hormone initiation, with a median PSA nadir of 0.05 ng/ml. Early initiation of hormone ablation resulted in statistically significant improvement in all outcome measures. Multivariate analysis indicated that PSA doubling time at hormone initiation was the most consistent predictor of outcome. The 5-year overall survival was 78% for patients whose androgen ablation was initiated at doubling time ≤7 months and 93% for patients when initiated at doubling time >7 months. Mean survival improved from 84.9 ± 4.6 (doubling time ≤7) to 115.3 ± 8.4 months (doubling time >7). Survival for patients started on hormones with doubling time <5 months was similar to that of patients with clinical metastases. Conclusions This survival benefit justifies the use of androgen ablation in patients whose doubling time approaches 7 months. A randomized trial is needed to confirm these findings, investigate potential benefit for patients with longer doubling times, and gather data on the morbidity of early hormone ablation, including quality of life issues.

Seminal vesicle involvement in patients with D1 disease predicts early prostate specific antigen recurrence and metastasis after radical prostatectomy and early androgen ablation.

Controversy persists regarding the management of patients who present with locally advanced metastatic prostate carcinoma. Although radical prostatectomy is not curative, there is growing evidence that survival may be prolonged when the surgery is combined with early androgen ablation. In the current study, the authors present data with which to evaluate and define factors for disease progression in patients undergoing radical prostatectomy with lymph node positive disease who are treated with early endocrine ablation. Data from 40 patients undergoing radical prostatectomy and early androgen ablation between 1987-1998, all of whom had lymph node positive disease, were analyzed. Age, preoperative prostate specific antigen (PSA) level, clinical and pathologic Gleason score, surgical margin, seminal vesicle involvement (SVI), and the number and percentage of involved positive lymph nodes were analyzed to predict PSA progression, metastasis, and death using univariate and multivariate statistical techniques. Univariate analysis identified only SVI as a statistically significant predictor of PSA progression and metastasis. Twenty-seven patients (67.5%) were found to have SVI. Multivariate analysis failed to identify other factors that added significantly to the predictive ability of SVI. Kaplan-Meier estimates of time to PSA recurrence and metastasis demonstrated that SVI was highly predictive of disease progression. The median time to PSA progression for the 27 patients with SVI was 7.5 years compared with no progression reported in the 13 patients without SVI (P = 0.011). VI is a very powerful predictor of disease progression in patients with lymph node positive disease who undergo radical prostatectomy and early androgen ablation. In the current study, preoperative PSA, clinical or pathologic Gleason scores, and other clinical factors were not found to be predictive of disease outcome.

Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer

Objectives. To determine the outcome for node-positive prostate cancer treated by early androgen ablation with or without prostatic radiation. Methods. Two hundred fifty-five men with lymphadenectomy-proven pelvic nodal metastases treated with early androgen ablation alone (n = 183) or with combined ablation and radiation (n = 72) between 1984 and 1998 were retrospectively reviewed for disease outcome and survival. Post-treatment disease status was based on the prostate-specific antigen levels or on the clinical and radiographic status for patients treated before 1987. Univariate and multivariate statistics were used to determine the prognostic factors and assess the influence of radiation treatment. Results. With a median follow-up of 9.4 years, the 5, 10, and 13-year overall survival rate for those treated with early ablation alone was 83%, 46%, and 21%, respectively. The freedom from relapse or rising prostate-specific antigen rate for these patients was 41%, 25%, and 19% at 5, 10, and 13 years, respectively. Distant metastasis and local recurrence occurred with a 10-year actuarial incidence of 44% and 51%, respectively. With a median follow-up of 6.2 years, the 5 and 10-year overall survival rate for those treated with radiation and ablation was 92% and 67%, respectively. The freedom from relapse or rising prostate-specific antigen rate in these men was 91% and 80% at 5 and 10 years, respectively. The superior outcome for combined ablation and radiation was substantial and statistically significant in the univariate and multivariate analyses. Conclusions. Early androgen ablation alone has little curative potential for node-positive prostate cancer. The addition of prostatic radiation to ablation resulted in substantial and significant improvement in disease control and patient survival.

LONG-TERM OUTCOME IN PATIENTS WITH pTxN+ ADENOCARCINOMA OF PROSTATE TREATED WITH RADICAL PROSTATECTOMY AND EARLY ANDROGEN ABLATION

Purpose We assessed retrospectively the outcome after bilateral pelvic lymphadenectomy and radical prostatectomy for pathological pTxN+ adenocarcinoma of the prostate when treated with or without adjuvant androgen ablation therapy. Materials and Methods A total of 790 men treated with radical prostatectomy for prostatic adenocarcinoma were found to have pTxN+ disease and treated further with or without androgen ablation therapy. Mean patient age was 64 years (range 40 to 79). Mean followup was 6.5 years, (range up to 25). Clinical stages were T2 or less in 60% of the cases, T3 in 38% and N+ in 2%. Gleason scores were 6 or less in 31% and 7 or greater in 69%. Deoxyribonucleic acid ploidy was diploid in 43%, tetraploid in 39% and aneuploid in 18%. Of the patients 96 (12%) received no androgen ablation therapy, with the remainder getting ablation therapy within 90 days of radical prostatectomy. Results Of the patients 186 (24%) died, with 109 (14%) dying of prostatic anedocarcinoma. Overall (and cause specific) survival probabilities at 5, 10 and 15 years were 87 (91), 69 (79) and 39% (60%), respectively. Patients with diploid tumors had better cause specific survival than those with nondiploid tumors (p = 0.009). Patients with diploid tumors were less likely to have progression biochemically, locally or systematically than those with nondiploid tumors (p = 0.038). Androgen ablation therapy had no effect on cause specific survival in nondiploid patients. Diploid patients treated with androgen ablation therapy for up to 10 years had no improvement in disease specific survival compared to those with no androgen ablation therapy. However, cancer death was significantly reduced after 10 years (p <0.002). The local control rate of pTxN+ cases that receive radical prostatectomy and androgen ablation therapy at 15 years is virtually identical to that of stage pT2c cases at our institution (79 +/− 3.0 versus 80% +/− 3.5%, respectively). There were no deaths secondary to radical prostatectomy, and complications were within the experience of that seen in patients with localized disease. Conclusions Radical prostatectomy with androgen ablation therapy is a viable option for patients with pTxN+ disease, particularly in view of excellent local control rates and low morbidity. Patients with diploid tumors have a more favorable outcome than those with nondiploid tumors when treated with androgen ablation therapy.

Effect of laparoscopic pelvic lymph node dissection on the natural history of D1 (T1-3, N1-3, MO) prostate cancer

Reports of abdominal wall tumor implantation after laparoscopic procedures have raised questions regarding the safety of laparoscopic surgery when applied to patients with malignancies. Our objective was to determine if laparoscopic pelvic lymph node dissection (LPLND) had a negative effect on tumor behavior and clinical outcome in men with Stage T1-3, N1-3, M0 (D1) prostate cancer. Fifty-two men were retrospectively identified at four institutions who had pelvic nodes positive for metastatic prostate adenocarcinoma at LPLND and at least 1 year of follow-up. Operative and clinical records were reviewed to determine morbidity, adjuvant treatment, onset of hormone-resistant disease, and survival. During a mean follow-up of 3.1 years, there were no cases of trocar site tumor implantation. There were four perioperative complications, including enterotomy, epigastric vessel injury, abscess, and symptomatic lymphocele formation. There were three deaths from prostate cancer (5.8%) occurring 3 to 4 years after LPLND. For the 45 men treated with early androgen ablation, the 5-year biochemical prostate-specific antigen and clinical progression free rates were 45% and 55%, respectively. Abdominal wall tumor implantation after LPLND for prostate cancer was not demonstrated, even in patients who developed hormone-resistant disease. LPLND in men with Stage D1 disease did not alter short-term disease progression. Longer follow-up in a larger cohort is necessary to determine if LPLND will have an impact on the 5 and 10-year disease progression and survival rates for patients with Stage D1 prostate cancer.

Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation

This study attempted to define unfavorable locoregional prostate carcinoma and presents the results of treatment with combined radiation and androgen ablation for these patients. Of a group of 938 men with clinically localized N0/NX disease treated with radiation alone, an unfavorable category included all men with prostate specific antigen (PSA) > 20 ng/mL and all men with 10 < PSA < or = 20 ng/mL but with Gleason's grade > 7. One hundred and eighty-five such men treated with radiation alone and an additional 100 men with similar disease received radiation with early androgen ablation. A second cohort was comprised of 229 men with lymphadenectomy proven pelvic lymph node metastases, with 185 receiving early androgen ablation alone and 44 receiving androgen ablation and local radiation. The outcomes, with recurrence or rising PSA as the endpoint, were compared among these various treatment groups using multivariate techniques. Disease outcome with the combined modality treatment was dramatically improved in both cohorts of men. For those with unfavorable N0/NX disease, the failure rate at 5 years decreased from 82% with only radiation therapy to 15% with combined treatment. Likewise, for patients with lymph node disease, the failure rate at 5 years decreased from 58% with only androgen ablation to 10% with combined treatment. For the whole group with unfavorable disease (unfavorable N0/NX and lymph node positive disease) the 6-year failure decreased from 71% with single modality treatment to 13% with bimodality treatment. There was a close relationship between the incidence of lymph node disease and prognostic categories and patients with otherwise unfavorable disease did not have their poor outlook ameliorated by undergoing a negative lymphadenectomy. Unfavorable locoregional prostate carcinoma can be recognized on the basis of pretreatment PSA level, T category, and Gleason's grade without specific evaluation of pelvic lymph node status. Combined local radiation and androgen ablation for patients with unfavorable disease results in a substantial improvement in disease control compared with that achieved by either modality alone. The authors found no improvement in survival because all groups of men had a normal life expectancy to at least 5 years.

Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer.

To compare disease progression and survival of patients with stage D1 adenocarcinoma after treatment with either early androgen ablation alone or combined with radical prostatectomy. A retrospective non-randomized study was performed in a series of 76 consecutive patients who underwent pelvic lymphadenectomy and had pathological stage D1 (T1-3, pN1-2, MO) prostate cancer; 37 patients underwent early endocrine therapy (EET) and 39 underwent radical prostatectomy with immediate adjuvant endocrine therapy (combined therapy, COM). The median follow-up was 3.8 years (range 0.26-13). The patients were statistically homogeneous for tumour grade, local tumour stage and nodal involvement, but not for age at lymphadenectomy (67 years and 62 years, respectively, P = 0.019, a confounding factor in favour of COM). Twelve patients (32%) in the EET group and 11 (28%) in the COM group died: the Kaplan-Meier actuarial overall survival curves showed no statistically significant difference between the treatment groups, but there was a trend in favour of the COM group. There was also no significant difference in the cause-specific survival. In the EET group, 17 men (46 %) had local (five of 37, 14%) or systemic (13 of 37, 35%) progression and in the COM group 23 patients (59%) had local (eight of 39, 21%) or systemic (20 of 39, 51%) progression. Four patients had an elevated level of prostate specific antigen with no clinical recurrence. Transurethral resection of the prostate was necessary for three (8%) patients in the EET group and for two (5%) of those receiving COM. The Kaplan-Meier actuarial disease-free survival curves were not significantly different. Similar results were obtained when the 25 patients with early-stage (T1 and T2) and the 51 patients with advanced primary tumours (T3 and T4) were analysed separately. These results suggest that in patients with stage D1 prostate cancer, radical prostatectomy combined with adjuvant endocrine therapy offers no advantage over endocrine therapy alone, neither for curative nor palliative intent.

Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation

Purpose : Patients with node-positive prostate cancer that is regionally localized (T1–4, N1–3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results radical surgery and androgen ablation have been reported, there are no date support an analogous approach using a local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM). Methods and Materials : Betweeb 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The Nodal status of all patients was establisged pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group. Results : The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA (46%), any disease progression (24%), and a rising PSA or disease progression (47%). Conclusion : Node-positive prostate cancer patients with regionally localized disease fared significantly better when combined local radiotherapy and early androgen ablation were used, as compared to early androgen ablation alone. Although the number of patients in the XRT/HORM group was small and follow-up was short, the combined treatment had a dramatic effect on disease outcome and, therefore, a larger prospective randomized trial is warranted.

Early Androgen Ablation for Stage D1 (N1 to N3, M0) Prostate Cancer: Prognostic Variables and Outcome

To elucidate the outcome for patients with stage D1 (N1 to N3, M0) prostate cancer we reviewed 179 patients with lymphadenectomy proved pelvic nodal metastases who underwent immediate androgen ablation as the only initial treatment. With a median followup of 43 months, the 5 and 8-year actuarial rates of freedom from disease progression were 55% and 25%, respectively, and the median interval to disease progression was 67 months. The 5 and 8-year survival rates were 85% and 57%, respectively. Median survival after disease progression was 36 months. Local and distant disease progression was equally important. At 5 and 8 years the incidence of local progression was 32% and 51%, respectively, while metastatic rates at the same intervals were 22% and 44%, respectively. Multivariate regression revealed that tumor grade and transurethral resection in preoperative stage C disease correlated with disease progression. Pretreatment prostate specific antigen (PSA) levels were not predictive of outcome. The fact that transurethral resection predicted for local as well as distant failure suggests that the procedure selects for rather than aggravates adverse disease. Posttreatment PSA levels were a sensitive index of response to treatment and of subsequent outcome. All patients who failed to achieve undetectable PSA levels had relapse by 8 years, whereas those whose levels became undetectable experienced only a 5% incidence of disease progression. These data show that androgen ablation alone is not curative for node positive disease but is associated with significant disease control and good short-term (5-year) survival. The primary tumor is an important source of androgen insensitive cells and comprehensive treatment strategies for this stage of disease require attention to the primary tumor as well as microscopic metastases.