Association between the pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic castration-resistant prostate cancer treated with ketoconazole was assessed. The pretreatment neutrophil-to-lymphocyte ratio and prostate-specific antigen doubling time, and prior response to androgen-deprivation therapy, were associated with the progression-free survival interval in these patients.
The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole.
This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis.
Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups.
In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.
Ketoconazole treatment; Metastatic castration-resistant prostate cancer; Neutrophil-to-lymphocyte ratio; Outcome; Predictive nomogram
Frequent PSA testing in screening and monitoring of prostate cancer has led to significant stage migration. We evaluated if overall survival (OS) in hormone naïve, metastatic prostate cancer patients has improved during the era of PSA use. We also assessed whether any subsets of patients benefited differentially during this period.
Materials and Methods
We compared OS in three sequential phase III trials of men with hormone naïve, metastatic prostate cancer receiving similar androgen deprivation therapy (n=3096): two conducted prior to the ‘PSA era’ (S8494 and S8894), and the other during this era (S9346). OS was adjusted for patient and disease risk factors in the latter two trials. Subgroups were evaluated by interactions of risk factors with trial.
Median OS in S8494 was 30 months, 33 months in S8894; and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 compared to S8894 (hazard ratio 0.78, 95% confidence interval 0.70, 0.87, p<0.001). The improvement in OS was greater in African Americans (AA) (p=0.008 for test of interaction). In both S8494 and S8894, median survival for AA was 27 months and 34 and 35 months for non-AA, respectively; this racial difference disappeared in S9346 (AA OS=48 months, non-AA OS=49 months).
Adjusting for risk factors, OS was significantly improved in the post-PSA era trial. However, attributing this solely to PSA monitoring cannot be concluded. AA men now have comparable OS to Caucasians. Current estimates of survival should be used for designing new trials in this population.
Cytotoxic chemotherapy; Metastatic castration-resistant prostate cancer; Docetaxel
Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-Lcysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa.
Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time- activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1.
Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (µGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 µSv/MBq (mean ± SD).
Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.
prostate-specific membrane antigen; prostate cancer; 18F; urea; PET/CT
To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants).
PATIENTS AND METHODS
Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed.
All patients received docetaxel either as clinical trial participants (n = 142; 11 separate studies) or as non-participants (n = 105).
Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation.
There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage.
Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P = 0.027) among trial participants vs non-participants.
Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial.
Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers’ attitudes because of greater contact with medical services.
With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.
prostate cancer; chemotherapy; clinical trial; metastatic castration-resistant prostate cancer; docetaxel; overall survival
To evaluate the prognostic significance of six epigenetic biomarkers (AIM1, CDH1, KIF1A, MT1G, PAK3 and RBM6 promoter hypermethlation) in a homogeneous group of prostate cancer patients, following radical prostatectomy.
Patients and Methods
Biomarker analyses were performed retrospectively on tumors from 95 prostate cancer patients all with a Gleason score of 3+4=7 and a minimum follow up period of 8 years. Using Quantitative Methylation Specific PCR (QMSP), we analyzed the promoter region of six genes in primary prostate tumor tissues. Time to any progression was the primary endpoint and development of metastatic disease and/or death from prostate cancer was a secondary endpoint. The association of clinicopathological and biomolecular risk factors to recurrence was performed using the Log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.
At a median follow-up time of 10 years, 48 patients (50.5%) had evidence of recurrence: biochemical/PSA relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression, the significant factors were: older age, HR=0.95 (95% CI: 0.91, 1.0) (P=0.03), positive lymph nodes HR=2.11 (95%CI: 1.05, 4.26) (P=0.04) and decreased hypermethylation of AIM1 HR=0.45 (95%CI: 0.2, 1.0) (P=0.05).
Methylation status of AIM1 in the prostate cancer specimen may predict for time to recurrence in Gleason 3+4=7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.
We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5mg or 25mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression.
Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect. Estimates were obtained using generalized estimating equations (GEE). Changes in circulating anti-prostate antibodies were evaluated using a high-throughput immunoblot technique.
Treatment with lenalidomide was associated with global changes in immune-reactivity to a number of prostate-associated antigens, as well as with changes in circulating levels of the TH2 cytokines IL-4, IL-5, IL-10 and IL-13. Disease progression in treated patients was associated with an increase in circulating IL-8 levels, while IL-8 levels decreased significantly in non-progressors.
Lenalidomide demonstrates immunomodulatory properties in patients with biochemically recurrent prostate cancer. The induction of novel anti-prostate antibodies is a potential mechanism for lenalidomide response. Changes in serum IL-8 levels may serve as a potential biomarker in treated patients. These hypotheses require formal testing in future prospective trials.
prostate cancer; antibody; cytokine; IL-8; lenalidomide
Several phase II trials in men with non-castrate PSA-recurrent prostate cancer have assessed the impact of novel non-hormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS).
We performed a retrospective post hoc analysis of 146 men treated in four phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n=39), imatinib (a tyrosine kinase inhibitor; n=25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n=22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n=60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation.
After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P=.05), baseline PSA slope (P=.01), on-study change in PSADT (P=.02), and on-study change in PSA slope (P=.03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% CI 34.6–not reached) and 28.9 months (95% CI 13.5–68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively.
This hypothesis-generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically-recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate endpoint for screening new agents in these patients.
AGS-1C4D4 is a human monoclonal antibody against prostate stem cell antigen (PSCA), a cell-surface protein expressed by most prostate cancers. AGS-1C4D4 is produced in Chinese hamster ovary (CHO) cells and has an identical sequence to AGS-PSCA, an anti-PSCA antibody produced in mouse hybridoma cells that has completed Phase I testing. Preclinical studies demonstrated comparability of AGS-1C4D4 to AGS-PSCA with respect to pharmacokinetics (PK) and tumor inhibition. However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK.
Patients and method
Thirteen patients with metastatic castration-resistant prostate cancer were enrolled. AGS-1C4D4 was administered intravenously every 3 weeks for four planned doses at 6, 12, 24, or 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints were immunogenicity and clinical activity. Disease assessments were conducted every 12 weeks and included radiographic and PSA evaluations. Patients with stable disease could receive extended treatment beyond four infusions.
Adverse events were primarily grade 1–2, without any grade 3–4 drug-related toxicities or infusion reactions. Anti-AGS-1C4D4 antibodies were not detected. Similar to AGS-PSCA, serum AGS-1C4D4 concentrations declined biphasically and elimination was characterized by slow clearance (CL) and a long terminal half-life (t1/2). Median CL for the four dose levels ranged from 0.10 to 0.14 ml/h kg, and t1/2 ranged from 2.2 to 2.9 weeks. No PSA reductions ≥50% were observed. Six patients (46%) had radiographically stable disease, lasting a median of 24 weeks.
AGS-1C4D4 was well-tolerated and demonstrated linear PK. Despite preclinical differences in antibody-dependent cellular cytotoxicity, AGS-1C4D4 and AGS-PSCA have similar safety and PK profiles. The recommended Phase II dose is 48 mg/kg.
AGS-1C4D4; Castration-resistant prostate cancer; Monoclonal antibody; Phase I; PSCA
Loss of the tumor suppressor PTEN is common in prostate cancer and may have prognostic significance. The authors examined PTEN and additional protein markers in primary tumors from patients with high-risk, localized prostate cancer who received adjuvant docetaxel in a prospective multicenter trial (TAX2501).
Fifty-six of 77 patients enrolled in TAX2501 had primary prostatectomy specimens available for immunohistochemical analysis of PTEN, MYC, ERG, tumor protein p53 (p53), antigen KI-67 (Ki67), and phosphorylated forms of Akt, mammalian target of rapamycin (mTOR), and S6 ribosomal protein. Protocol-defined progression included a prostate-specific antigen (PSA) level ≥0.4 ng/mL, radiologic/clinical recurrence, or death. Univariate and multivariable proportional hazards regression analyses were used to investigate the influence of PTEN status (and other protein markers) on progression-free survival (PFS).
In this exploratory, post hoc analysis, PTEN protein loss (vs presence) was observed in 61% of patients and was associated with lower preoperative PSA levels, higher clinical stage, lower Ki67 expression, the presence of p53, and the presence of ERG. In univariate analysis, the factors associated with PFS included Gleason sum, seminal vesicle invasion, PTEN status, MYC expression, and Ki67 expression. In multivariable analysis, only 3 variables emerged as independent prognostic factors for PFS: PTEN status (P = .035), MYC expression (P = .001), and Ki67 expression (P < .001). A prognostic model was constructed that incorporated clinical covariates as well as information on PTEN, MYC, and Ki67.
The current results indicated that PTEN status, MYC expression, and Ki67 expression in primary tumor samples may predict PFS more accurately than clinical factors alone in men with high-risk prostate cancer who receive adjuvant docetaxel after prostatectomy. If validated, these hypothesis-generating findings may have prognostic and therapeutic implications and may aid clinical trial design.
PTEN; MYC; Ki67; high-risk prostate cancer; adjuvant docetaxel; progression-free survival; prognostic model
To describe metastasis-free survival (MFS) in men with prostate-specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk.
PATIENTS AND METHODS
We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease.
We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression.
Median follow-up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow-up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years.
Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (<3.0 vs 3.0–8.9 vs 9.0–14.9 vs ≥15.0 months) and Gleason score (≤6 vs 7 vs 8–10).
Using these stratifications of Gleason score and PSA doubling time, tables were constructed to predict median, 5- and 10-year MFS after PSA recurrence. In different patient subsets, median MFS ranged from 1 to 15 years.
In men undergoing prostatectomy, MFS after PSA recurrence is variable and is most strongly influenced by PSA doubling time and Gleason score. These parameters serve to stratify men into different risk groups with respect to metastatic progression.
Our findings may provide the background for appropriate selection of patients, treatments and endpoints for clinical trials.
metastasis-free survival; natural history; prostate cancer; PSA recurrence
The TAX 327 trial was pivotal in establishing docetaxel in castration refractory metastatic prostate cancer. Various commonly prescribed and over-the-counter co-administered medications are thought to exhibit anti-neoplastic properties and/or could potentially have pharmacokinectic interactions with docetaxel lessening the effectiveness of chemotherapy.
To examine the effect of on prostate cancer outcomes within this trial, we examined overall survival, prostate-specific antigen (PSA) response, percent PSA reduction, pain response and QOL responses for 14 families of medications including metformin, digoxin, verapamil, proton pump inhibitors, nitrates, statins, cox-2 inhibitors, warfarin, heparins, ascorbic acid, selenium, tocopherol, antidepressants and erythropoietin.
Our findings did not reveal any medication that had a significant additive or synergistic effect with docetaxel. We did note, however, that patients on digoxin or verapamil had poorer overall survival, possibly due to a trend of fewer cycles of administered chemotherapy being administered to the verapamil group, consistent with a pharmacokinectic interaction.
These data are only hypothesis-generating given the statistical limitations, but may form a basis for similar future analysis in other malignancies. The data suggest the need to be aware of pharmacokinectic interactions with medications that may interact with docetaxel.
This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of 153Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).
mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m2 (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m2. 153Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).
Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of 153Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.
Concurrent 6-month administration of 4 doses (75 mg/m2) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg 153Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.
153Sm-lexidronam; Metastatic prostate cancer; Docetaxel; Phase I
In men with metastatic castration-resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation.
Eligible patients for this analysis included those with World Health Organization (WHO)-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated by using the Kaplan-Meier method, and the prognostic relation of WHO-defined radiologic response with OS was performed by using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and at 2, 3, 4, and 6 months after baseline.
Four hundred twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD, 24%) and 160 (38.8%) did not have a after-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. The authors found a significant association between ≥30% prostate-specific antigen (PSA) declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD, and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ≥30% PSA decline (P = .009).
In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS and appeared to complement PSA assessment.
castration-resistant prostate cancer; measurable disease; WHO response; PSA response; overall survival
The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear.
A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS).
Design, setting, and participants
An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles.
Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion.
Results and limitations
The number of men receiving 10 cycles was similar (p = 0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9–95.4%) and 74.6% (CI, 67.2–80.5%) in TAX-327, compared with 92.8% (CI, 85.5–96.5) and 63.4% (CI, 51.8–72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply.
A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.
Docetaxel; Prednisone; Metastatic castration-resistant; prostate cancer
Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). The neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, is associated with outcome in several cancer types.
To study the association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival (PFS) and overall survival (OS) of patients treated with sunitinib for mRCC.
We retrospectively studied an unselected cohort of patients with mRCC, who were treated with sunitinib. Logistic regression model was used to analyse response rate. Cox regression models were fitted to identify risk factors associated with PFS and OS. We investigated how pre-treatment NLR is associated with these clinical outcomes after adjusting for confounding covariates. Regression tree for censored data method was used to find the best NLR cut-off value.
Between 2004 and 2011, 133 patients with mRCC were treated with sunitinib. One hundred and nine were included in the NLR analysis, from which were excluded patients without available data on pre-treatment NLR or with comorbidities/recent treatments known to be associated with a change of blood counts. Factors associated with PFS were low NLR ≥ 3 (HR = 0.285, p < 0.001), past nephrectomy (HR = 0.38, p = 0.035), sunitinib dose reduction/treatment interruption (HR = 0.6, p = 0.014), and the use of antiotensin system inhibitors (HR = 0.537, p = 0.008). Low NLR ≥ 3 was associated with OS (HR = 0.3, p = 0.043).
In patients with mRCC treated with sunitinib, pre-treatment NLR may be associated with PFS and OS. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Metastatic renal cell carcinoma; Neutrophil to lymphocyte ratio; Outcome; Sunitinib
Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk–benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.
Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.
A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.
Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone–releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.
Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk–benefit ratio.
Prostate cancer; Androgen deprivation; Hormone treatment; Adverse effects
Adrenal/intratumoral androgen biosynthesis contributes to ligand-dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole.
Data were retrospectively analyzed in all mCRPC patients treated with ketoconazole. Patients continued GnRH-agonist, and treated with ketoconazole 200–400 mg 3× a day until dose-limiting toxicity or disease progression. A multivariate cox regression model was used to identify clinical factors associated with PSA response and disease progression.
From 1999 to 2010, 114 mCRPC patients were treated with ketoconazole. With a median follow-up time of 31 months (range 5–129), 25 patients (22%) had grade 3/4 toxicity, most commonly fatigue, abdominal discomfort, nausea, and dizziness. Sixty-one patients (54%) had ≥50% PSA decline. Median time to progression was 8 months (range 1–129). Factors associated with PSA response and disease progression were response to prior antiandrogen (≥6 vs. <6 months), pre-treatment PSADT (≥3 vs. <3 months) and extent of disease (limited-axial skeleton and/or nodal vs. extensive-appendicular skeleton and/or visceral).
Ketoconazole is effective and safe in mCRPC. Prior response to antiandrogen, pre-treatment PSADT, and disease extent are associated with PSA response and disease progression, and further supports a therapeutic role in suppressing adrenal androgens in mCRPC.
disease progression; ketoconazole; metastatic castration-resistant prostate cancer; PSA response
To evaluate the pathologic outcome of prostate-specific antigen-screened patients with high-grade (Gleason score ≥ 8) prostate cancer limited to 1 biopsy core, without clinical evidence of disease.
Ninety-two patients with only 1 biopsy core with cancer and treated by radical prostatectomy were divided into 4 groups according to the biopsy Gleason score: 3 + 3 = 6 (23 cases), 3 + 4 = 7 (25 cases), 4 + 3 = 7 (20 cases), and ≥8 (24 cases).
Cases with Gleason score ≥8 showed a significantly higher proportion of extraprostatic extension (50%), positive surgical margins (21%), and seminal vesicle invasion (12%) when compared with the other groups. Patients with Gleason score ≥8 in the biopsy had a 25-fold increased in the odds ratio for extraprostatic extension in the prostatectomy. The incidence of extraprostatic extension was higher in those with prostatic cancer involving ≥50% of one core (88%) compared with cases involving <50% (32%).
In patients with prostate cancer limited to 1 biopsy core, the presence of Gleason score ≥8 significantly increased the incidence of extraprostatic extension, positive surgical margins, and seminal vesicle invasion. The odds ratio was substantially higher in patients with ≥50% of Gleason ≥8 in the biopsy core. These data might be taken into account for proper clinical management of this set of patients.
To determine the agreement between the local pathologist findings and central pathologist findings using data from the TAX 3501 trial. TAX 3501 was a randomized, multinational trial comparing the outcomes of patients with high-risk prostate cancer treated with androgen deprivation with or without docetaxel after radical prostatectomy (RP). Patient eligibility was determined by a minimal 5-year progression-free survival estimate of 60% using Kattan’s nomogram.
The pathologic findings were reassessed in 257 consecutive RP specimens by 2 central pathologists and compared with the local pathologist data.
For the Gleason score, agreement was found in 181 (70%) of 257 cases, upgrading in 57 (75%), and downgrading in 25% of the RP specimens The most frequent upgrade was from Gleason score 7 to 8 or 9 and downgrading from Gleason score 8 to 7. Of the upgrades and downgrades, 37% and 21% were of 2 Gleason score points, respectively. For the tumor extent, agreement was found in 179 (70%) of 256 specimens, with upstaging in 70 (91%) and downstaging in 9%. The most frequent upstage was from focal to extensive extraprostatic extension (45%). For seminal vesicle invasion, agreement was found for 238 (93%) of 256 RP specimens Almost equal rates of underdiagnosing and overdiagnosing seminal vesicle invasion was observed. For margin status, agreement was present for 229 (89%) of 256 cases. The central pathologist review led to reclassification as a positive margin in 17 cases and a negative margin in 10. For lymph node status, 2 (1%) of 210 RP specimens had positive nodes identified only by the central pathologist. Agreement was observed in 154 negative and 54 positive cases.
Significant interobserver variations were found between the central and local pathologists. From the central pathologist review, the progression-free survival estimates were altered in 31 patients (13%), including 22 who were reassigned a greater risk estimate, rendering them study eligible. Thus, interobserver variability affected prognostication and trial accrual.
To evaluate the safety and activity of 6 months of treatment with lenalidomide at 5 or 25 mg/d in nonmetastatic biochemically relapsed prostate cancer.
Sixty men with non-castrate, nonmetastatic, biochemically relapsed prostate cancer were stratified by prostate-specific antigen (PSA) doubling time, surgery/radiation therapy, prior androgen deprivation therapy (ADT), and randomized to lenalidomide 5 mg (n = 26) or 25 mg/d (n = 34) for 3 weeks repeated monthly for 6 months or until dose-limiting toxicity or disease progression. Toxicity was evaluated monthly, and PSAs and X-rays/scans every 6 months. Study size was determined to detect a progression rate of 40% at 6 months in either arm with 85% power (compared with a rate of 80% in the population receiving no treatment). Changes in PSA slopes were calculated using the regression of the log PSA for each patient before and during the initial 6 months and compared by t test.
Baseline variables were balanced between arms. Grade 3/4 toxicity rates were 12% (n = 3) with 5 mg and 29% (n = 10) with 25 mg (P = 0.1), most commonly neutropenia (five patients, all on 25 mg). Two patients per arm had thromboembolic events. The change in PSA slope was greater with 25 mg versus 5 mg [−0.172 (−0.24 to −0.11) versus −0.033 (−0.11 to 0.04); P = 0.005]. With a mean follow-up of 31.4 months (range 14–44), five patients on 25 mg and one patient on 5 mg remain on the study.
Lenalidomide has acceptable toxicity and is associated with long-term disease stabilization and PSA declines. Randomized studies evaluating conventional clinical disease end points in this patient population are planned.
We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipu-leucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes.
In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy).
PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion.
We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of bio-markers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions.
A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit.
Castration-resistant prostate cancer; Biomarkers; Prognosis; Surrogate; Circulating tumor cells; PSA; Bone turnover markers; Progression-free survival
To describe metastasis-free survival (MFS) and overall survival (OS) among men with prostate-specific antigen (PSA)-recurrent prostate cancer after radical prostatectomy who did not receive additional therapy until metastasis, using a multicentre database capturing a wide ethnic mix.
PATIENTS AND METHODS
A retrospective analysis of the Center for Prostate Disease Research National Database (comprised of five US military hospitals and one civilian centre) was performed for patients with PSA relapse (≥0.2 ng/mL) after radical prostatectomy who had no additional therapy until the time of radiographic metastatic disease.
We investigated factors influencing metastasis and all-cause mortality using univariate and multivariate Cox regression analysis.
There were a total of 346 men who underwent radical prostatectomy between May 1983 and November 2008 and fulfilled the entry criteria. All patients had information on survival and 190 men had information on metastasis. Among patients with survival data (n = 346), 10-year OS was 79% after a median follow-up of 8.6 years from biochemical recurrence.
Among men with metastasis data (n = 190), 10-year MFS was 46% after a median follow-up of 7.5 years.
In Cox regressions, four clinical factors (Gleason score, pathological stage, time to PSA relapse and PSA doubling time), as well as age, were predictive of OS and/or MFS in univariate analysis, although only PSA doubling time (≥9 vs 3–8.9 vs <3 months) remained independently predictive of these outcomes in multivariate analysis (P < 0.001).
This multicentre multi-ethnic dataset shows that OS and MFS can be extensive for men with PSA-recurrent prostate cancer, even in the absence of further therapy before metastasis.
This unique patient cohort, the second largest of its type after the Johns Hopkins cohort, confirms that PSA doubling time is the strongest determinant of OS and MFS in men with PSA-recurrent disease.
Longer follow-up and more events will be required to determine whether other variables may also contribute to these outcomes.
metastasis-free survival; natural history; overall survival; prostate cancer; PSA recurrence
Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial.
Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration.
A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response.
These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients.
antiandrogen withdrawal; prostate cancer; PSA; prognosis; survival; secondary hormonal therapy; hormone-refractory prostate cancer