Impact of Neoadjuvant Prostate-Specific Antigen Kinetics on Biochemical Failure and Prostate Cancer Mortality: Results From a Prospective Patient Database

doi:10.1016/j.ijrobp.2012.04.009

International Journal of Radiation OncologyBiologyPhysics

Volume 85, Issue 2, 1 February 2013, Pages 385-392

Presented in part at the 52nd Annual Meeting of the American Society for Radiation Oncology (ASTRO) San Diego, CA, October 31-November 4, 2010.

https://doi.org/10.1016/j.ijrobp.2012.04.009 Get rights and content

Purpose

To confirm findings from an earlier report showing that neoadjuvant (NA) prostate-specific antigen (PSA) halving time (PSAHT) impacts biochemical failure (BF) rates, and to examine its association with prostate cancer-specific survival (PCSS), in a large prospective cohort of patients.

Methods and Materials

A total of 502 patients were selected from a prospective database, who had localized prostate adenocarcinoma treated with 2-12 months of neoadjuvant androgen deprivation therapy (N-ADT) followed by external beam radiation therapy (EBRT) between 1994 and 2000, and had at least 2 NA PSA values. Seventy-four percent of patients had high-risk prostate cancer. Median initial PSA value, N-ADT duration, total ADT duration, and radiation therapy dose were 14 ng/mL, 6.9 months, 10.8 months, and 68 Gy, respectively.

Results

At a median follow-up of 9.9 years, 210 patients have had a BF. Median PSAHT was 18 days. On univariate analysis, PSAHT was not shown to predict for BF (P=.69) or PCSS (P=.28). However, NA nadir PSA (nanPSA) and post-therapy nadir PSA (ptnPSA), when analyzed as continuous or categoric variables, predicted for BF (P<.001) and PCSS (P<.001). On multivariate analysis, nanPSA (P=.037) and ptnPSA (P<.001) continued to be significantly associated with BF. However, N-ADT duration lost significance (P=.67), and PSAHT remained a nonsignificant predictor (P=.97). For PCSS, multivariate analysis showed nanPSA (P=.049) and ptnPSA (P<.001) to be significant. Again PSAHT (P=.49) remained nonsignificant.

Conclusions

In this large, prospective cohort of patients, NA PSA kinetics, expressed as PSAHT, did not predict BF or PCSS. However, nadir PSAs, in both the NA and post-therapy settings, were significant predictors of BF and PCSS. Optimization of therapy could potentially be based on early PSA response, with shorter durations of ADT for those predicted to do favorably, and intensification of therapy for those likely to have poorer outcomes.

Introduction

Neoadjuvant androgen deprivation (N-ADT) has been shown to improve biochemical outcomes in patients with localized prostate adenocarcinoma undergoing external beam radiation therapy (EBRT) (1). However, its optimum duration is still unclear, and there have been conflicting data from randomized and population-based studies regarding its potential adverse effects 2, 3. Namely, a pooled analysis from 3 randomized trials showed a shorter time to fatal myocardial infarction in older men receiving 6 months of N-ADT. A further report using the Surveillance, Epidemiology, and End Results database of 73,196 patients suggested a higher risk of diabetes, coronary artery disease, myocardial infarction, and sudden cardiac death with the use of ADT.

Prostate-specific antigen (PSA) kinetics in the post-therapy setting has been shown to predict outcomes, especially after biochemical failure (BF). In addition, a number of more recent reports have examined and correlated the impact of PSA response during N-ADT, expressed as a nadir PSA value, on outcomes. However, PSA kinetics during N-ADT before EBRT has been less well described.

In 2010, Malik et al (4) first reported on the impact of PSA kinetics during N-ADT on biochemical outcomes in a retrospective analysis of 117 men. They showed that a faster PSA decline (expressed as a shorter PSA halving time [PSAHT]) during N-ADT and before EBRT was associated with lower BF rates. In particular, men with a PSAHT <2 weeks had a 4-year PSA control rate of 96%, vs 81% for those men with PSAHT >2 weeks.

This study aimed to validate this finding in a larger, prospectively followed cohort of patients.

Section snippets

Patients

Eligible patients with localized prostate adenocarcinoma were treated at our institution between June 1994 and January 2001 and followed as part of a prospective study. This database was set up to prospectively collect baseline treatment and follow-up information on a cohort of patients undergoing curative EBRT, with the sole inclusion criterion being the availability and willingness of the patient to attend for routine follow-up. Patients were seen 6 weeks after the completion of EBRT, then

Results

A total of 502 patients with at least 2 PSA values were eligible for analysis. Baseline characteristics are outlined in Table 1.

The median PSAHT was 18.4 days. The distribution of PSAHT was as follows: 0-2 weeks (n=152), 2-4 weeks (n=195), >4 weeks (n=100). Fifty-five patients had a rising NA PSA level. Median interval between start of N-ADT and first NA PSA level was 79 days. Median interval between the last NA PSA level and start of radiation therapy was 50 days. Median N-ADT duration was 6.9

Discussion

The present study comprises a large cohort of patients from a prospective database with extended follow-up. Our findings that PSAHT and NA PSA slope do not significantly predict for BF or PCSS contrast with those reported by Malik et al (4).

A number of differences between the 2 studies may have influenced this and warrant further discussion. First, the present group of patients shows poorer prognostic features, with 50% of all patients having ≥T3 primary tumors, and 74% were in the high-risk

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Cited by (13)

Early biochemical predictors of survival in intermediate and high-risk prostate cancer treated with radiation and androgen deprivation therapy
2019, Radiotherapy and Oncology
To identify early biochemical predictors of survival in intermediate- and high-risk prostate cancer patients with a pre-treatment PSA <20 ng/mL following definitive radiation therapy (RT) and androgen deprivation therapy (ADT).
A single-institution review of 2566 intermediate and high-risk prostate cancer patients treated with definitive RT and neoadjuvant and concurrent ADT from 1990 to 2012 was performed. The first prostate-specific antigen (PSA) value within three months of ADT initiation (post-ADT PSA) and the first PSA within three months after RT completion (post-RT PSA) were recorded. 1275 had baseline PSA <20 ng/mL and either post-ADT or post-RT PSA available. Median follow-up was 7.6 years. The relationship between post-treatment PSA kinetics and biochemical relapse (BR), distant metastasis (DM), prostate cancer specific death (PCSD) and overall survival (OS) was modeled using Cox regression univariate and multivariate analysis (MVA).
MVA demonstrated a strong association between a post-RT PSA ≥0.09 ng/mL and a significantly higher risk of BR (HR: 1.93; 95% CI: 1.45–2.57; p < 0.001), DM (HR: 2.97; 95% CI: 2.01–4.39; p < 0.001), PCSD (HR: 2.99; 95% CI: 1.73–5.15; p < 0.001) and OS (HR: 1.49; 95% CI: 1.18–1.86; p < 0.001). Post-RT PSA reduction of ≥95% relative to the baseline PSA was associated with a significantly lower risk of BR (MVA HR: 0.58; 95% CI: 0.41–0.83; p = 0.003) and DM (MVA HR: 0.47; 95% CI: 0.30–0.76; p = 0.002).
A PSA value ≥0.09 ng/mL early after RT completion is associated with significantly worse prognosis across all clinical outcomes, and an early PSA reduction of ≥95% is associated with reduced risk of BR and DM. These findings may identify patients who require early aggressive systemic management for high-risk disease.
Prostate-Specific Antigen After Neoadjuvant Androgen Suppression in Prostate Cancer Patients Receiving Short-Term Androgen Suppression and External Beam Radiation Therapy: Pooled Analysis of Four NRG Oncology Radiation Therapy Oncology Group Randomized Clinical Trials
2019, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Hussain et al32 noted also that the risk of death was less with lower nadir PSA values after induction AS in Intergroup randomized clinical trial INT-0162. Other studies investigated the prognostic value of PSA level at the end of short-term AS and RT,4,11,14,21 which was at (or close to) the end of RT or at the end of AS if it was given briefly thereafter. The pooled secondary analysis of the Dana Farber Cancer Institute trial 95096 and the Trans-Tasman Radiation Oncology Group trial 96.01 by D'Amico et al21 is particularly noteworthy in this regard.
To validate whether prostate-specific antigen (PSA) level after neoadjuvant androgen suppression (neoAS) is associated with long-term outcome after neoAS and external beam radiation therapy (RT) with concurrent short-term androgen suppression (AS) in patients with prostate cancer.
This study included 2404 patients. The patients were treated with neoAS before RT and concurrent AS (without post-RT AS) and were pooled from NRG Oncology/RTOG trials 9202, 9408, 9413, and 9910. Multivariable models were used to test associations between the prespecified dichotomized post-neoAS, pre-RT PSA level (≤0.1 vs >0.1 ng/mL) groupings, and clinical outcomes.
The median follow-up for surviving patients was 9.4 years. The median post-neoAS, pre-RT PSA level was 0.3 ng/mL, with 32% of patients having levels ≤0.1 ng/mL. Race, Gleason score, tumor stage, node stage, pretreatment PSA level, and duration of neoAS were associated with the groups of patients with PSA levels ≤0.1 and >0.1 ng/mL. In univariate analyses, post-neoAS, pre-RT PSA level >0.1 ng/mL was associated with increased risks of biochemical failure (hazard ratio [HR], 2.04; P < .0001); local failure (HR, 2.51; P < .0001); distant metastases (HR, 1.73; P = .0006); cause-specific mortality (HR, 2.36; P < .0001); and all-cause mortality (HR, 1.24; P = .005). In multivariable models that also included baseline and treatment variables, post-neoAS, pre-RT PSA level >0.1 ng/mL was independently associated with increased risk of biochemical failure (HR, 2.00; P < .0001); local failure (HR, 2.33; P < .0001); and cause-specific mortality (HR, 1.75; P = .03).
Patients with a PSA level >0.1 ng/mL after neoAS and before the start of RT had less favorable clinical outcomes than patients whose PSA level was ≤0.1 ng/mL. The role of post-neoAS, pre-RT PSA level relative to PSA levels obtained along the continuum of medical care is not presently defined but could be tested in future clinical trials.
Prognostic value of biochemical response to neoadjuvant androgen deprivation before external beam radiotherapy for prostate cancer: A systematic review of the literature
2016, Cancer Treatment Reviews
Citation Excerpt :
Considering that most of the analyzed patients were at high-risk and excluding the first series of Zelefsky et al., reporting on 213 patients treated between 1989 and 1995 [14], the rest of the more recently published series reported biochemical control rates at 5 years of more than 80% for patients reaching a PSA nadir before RT. This difference was independent from the RT dose delivered, as observed both for RT series delivering conventional dose (⩽70 Gy) [15,16,18,19,24] or dose-escalated (⩾74 Gy) [20–22,38] schedules using modern RT techniques. More importantly, the prognostic impact of PSA response to the nADT was observed for survival endpoints like DMFS, CSS, and OS.
External beam radiation therapy (EBRT) in combination with androgen deprivation therapy (ADT) is considered a standard treatment option for patients with aggressive localized and locally-advanced prostate cancer. Randomized phase III trials have provided evidence for combining EBRT to short-term ADT for intermediate-risk disease and to long-term ADT for patients harboring high-risk tumors. Even if several improvements and developments have been made in the last years in terms of radiotherapy delivery techniques, image-guided radiotherapy, and better sparing of the organs at risk the current use of ADT remains still linked to a therapeutic algorithm based on the prostate cancer risk classification as proposed by clinical trials.
Emerging literature has recently shown that the biochemical response to a course of neoadjuvant ADT before EBRT, called the “prostate-specific antigen (PSA) nadir” (lowest value after treatment), may influence the long-term biochemical tumor-control outcomes of prostate cancer patients. An individualized approach adapting the duration of hormonal treatment according to the PSA response during the neoadjuvant phase, as well using new generation hormonal agents, may represent a new therapeutic strategy and a future way to improve the therapeutic ratio for prostate cancer patients.
In this systematic review of the literature we explored the prognostic value of the PSA response to the neoadjuvant ADT phase and the rationale to adjust the use of ADT and EBRT in patients with intermediate- and high-risk prostate cancer based on the biochemical response to the neoadjuvant androgen ablation phase.
The significance of metabolic response to neoadjuvant androgen deprivation therapy detected with [<sup>68</sup>Ga]Ga-PSMA-11-PET/CT in high-risk prostate cancer patients treated with definitive radiotherapy
2023, European Journal of Nuclear Medicine and Molecular Imaging
Early biochemical outcomes following neoadjuvant/adjuvant relugolix with stereotactic body radiation therapy for intermediate to high risk prostate cancer
2023, Frontiers in Oncology
Adjusting the duration of androgen deprivation therapy (ADT) based on nadir PSA for high risk localized prostate cancer patients treated with definitive external beam radiation therapy and ADT
2022, BMC Urology

View all citing articles on Scopus

: Conflict of interest: none.

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Clinical InvestigationImpact of Neoadjuvant Prostate-Specific Antigen Kinetics on Biochemical Failure and Prostate Cancer Mortality: Results From a Prospective Patient Database

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Urology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Impact of Neoadjuvant Prostate-Specific Antigen Kinetics on Biochemical Failure and Prostate Cancer Mortality: Results From a Prospective Patient Database