Chemotherapy In Castration-resistant Prostate Cancer Patients Research Articles

Improved efficacy of mitoxantrone in patients with castration-resistant prostate cancer after vaccination with GM-CSF-transduced allogeneic prostate cancer cells

ABSTRACT Previous vaccination studies in patients with castration-resistant prostate cancer (CRPC) showed improved survival without prolongation of progression-free survival (PFS). This might be explained by enhanced efficacy of subsequent therapies because of heightened immune status. We therefore evaluated the efficacy of chemotherapy in CRPC patients after immunotherapy. We retrospectively analyzed 28 patients who were treated with ipilimumab and GVAX, an allogeneic vaccine, and 21 patients who were randomized to GVAX or no vaccination. To study whether immune status was related to the efficacy of chemotherapy, frequencies of myeloid and lymphocyte subsets were determined. Of 28 patients treated with GVAX and ipilimumab, 23 patients received docetaxel and 13 patients mitoxantrone. Median PFS after docetaxel was 6.4 mo (range 0.8–11.2), while median PFS after mitoxantrone was markedly longer than expected (4.8 mo; range 1.4–13.7). High CD8+ICOS+ Tcell/Treg and pDC/mMDSC ratios were associated with relatively long PFS after mitoxantrone, suggesting a correlation between activated immune status and benefit of mitoxantrone. Analysis of 21 patients, randomized to GVAX or not, revealed a median PFS after docetaxel of 9.9 mo for vaccinated patients and 7.1 mo for unvaccinated patients. Interestingly, PFS after mitoxantrone (n = 14) was significantly longer in vaccinated patients as compared to controls (5.9 vs. 1.6 mo, p = 0.0048). In conclusion, mitoxantrone seems more effective in CRPC patients after immunotherapy, which may be related to the immune-stimulating effect of mitoxantrone in patients with heightened antitumor immunity. As this was a retrospective study with limited sample size, prospective studies are warranted to definitively show proof of principle.

Exponential rise in prostate-specific antigen (PSA) during anti-androgen withdrawal predicts PSA flare after docetaxel chemotherapy in patients with castration-resistant prostate cancer.

PurposeTo investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC).Materials and MethodsThis study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1.ResultsThere were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034).ConclusionAn exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.

Serum alkaline phosphatase differentiates prostate-specific antigen flare from early disease progression after docetaxel chemotherapy in castration-resistant prostate cancer with bone metastasis.

A transient rise in prostate-specific antigen (PSA) after the initiation of chemotherapy, called as PSA flare, has been frequently reported in patients with castration-resistant prostate cancer (CRPC) but there has been no way to differentiate PSA rises in CRPC. We investigated whether bone-related serum markers differentiate PSA flare from progression in CRPC patients with bone metastasis. We reviewed CRPC patients with bone metastasis who received systemic chemotherapy from 2002 to 2008. Pretreatment baseline and follow-up data including age, performance score, PSA, Gleason score, alkaline phosphatase (ALP), calcium level, and hemoglobin were evaluated. Pretreatment parameters and follow-up serum parameters after the first cycle of chemotherapy were included in statistical analyses. PSA increased in 38 patients (45.8 %) at the first evaluation after chemotherapy. Among the PSA rises, PSA increased continuously or did not decrease to the stabilization level by the third evaluation in 22 (26.5 %) patients, while PSA decreased to the stabilization or response level by the third evaluation in 16 (19.3 %). PSA flare occurred in 17 (20.5 %). The univariate analyses showed that no baseline parameters were associated with PSA flare, but the initial ALP decrease, changed ALP ratio, and median calcium level were significantly associated with PSA flare (p = 0.001, p = 0.008 and p = 0.012, respectively). Multivariate logistic regression analysis showed that a change in the ALP level is an independent predictive factor for PSA flare (p = 0.017). ALP is a useful biomarker to differentiate PSA flare from early PSA progression during docetaxel chemotherapy in CRPC patients with bone metastasis.

Influence of Nonregional Lymph Node Metastasis as a Prognostic Factor in Metastatic Prostate Cancer Patients

PurposeIn advanced prostate cancer, malignant cells generally tend to spread into the bone, and metastasis into nonregional lymph nodes (NRLNs) at the time of initial diagnosis is relatively rare. We investigated the prognostic significance of NRLN metastasis in patients receiving hormonal therapy and chemotherapy.Materials and MethodsFrom February 2005 to August 2011, we identified 105 patients who had metastatic prostate cancer. First, we assessed the prognostic effect of NRLN metastasis on the prostate-specific antigen response through logistic regression and the progression-free time to castration-resistant prostate cancer (CRPC) by using the Cox proportional hazard regression model. Second, we investigated the prognostic influence of NRLN metastasis on the chemotherapy response through logistic regression and on cancer-specific survival of CRPC patients receiving chemotherapy by using Cox proportional analysis.ResultsOf these 105 patients, 12 patients (11.4%) had only NRLN metastases without bone metastases. Progression-free time to CRPC was significantly less in patients with NRLN metastases by Cox proportional hazard regression multivariate analysis (p=0.020). However, NRLN metastasis was not an independent factor for predicting the response to chemotherapy in CRPC patients, and NRLN metastasis did not reduce cancer-specific survival in the multivariate analysis.ConclusionsTwelve (11.4%) of 105 patients with NRLN metastases had lymph node metastases without bone metastases. In addition, NRLN metastasis was a significant prognostic factor for predicting reduced progression-free time to CRPC. Thus, although we speculate that prostate cancer with NRLN metastasis exhibits unique tumor biology, additional molecular and genetic studies are needed.

Docetaxel-Based Chemotherapy in Elderly Patients (Age 75 and Older) with Castration-Resistant Prostate Cancer

There are no data on the patterns of care and outcome of very elderly patients with castration-resistant prostate cancer (CRPC) treated with docetaxel. To assess the routine use of first-line docetaxel-based chemotherapy in CRPC patients aged >75 yr. We reviewed the clinical files of 175 patients aged > or =75 yr with CRPC treated with first-line docetaxel in nine French tertiary care cancer centres from 2000 to 2007. Response rate, survival, and adverse events (AE). Median age was 78 yr. Ninety-five patients (54%) received a standard 3-wk regimen (SR), and 80 patients (46%) received an adapted regimen (AR) delivered on a weekly schedule with various times for rest periods. Patients treated with an AR were older (>80 yr) and had poorer performance status (PS; > or =2) than patients treated with the SR. The prostate-specific antigen (PSA) response rates were not significantly different between the standard and adapted treatment groups (71% vs 68%, p=0.79). The median progression-free survival (PFS) was 7.4 mo. The median overall survival (OS) was 15 mo. The incidence of grade 3 or 4 AEs was 46% and was correlated with poor PS and the presence of visceral disease but not with the regimen. Early discontinuation of treatment because of toxicity occurred more frequently in the AR group than in the SR group (30% vs 8.4%, p=0.0005). In multivariate analysis, only PS and the presence of visceral disease were predictors of OS. Docetaxel is active and feasible in elderly patients with good PS. The optimal treatment of frail patients with CRPC remains to be established. Geriatric tools should be used to more accurately detect elderly CRPC patients who are unfit for chemotherapy. Age by itself should not be used as a criterion to deny patients with CRPC a potentially effective chemotherapy.