Long-term Adjuvant Androgen Deprivation Research Articles

Phase III Study of Hypofractionated, Dose Escalation Radiotherapy vs. Conventional Pelvic Radiation Therapy followed by High Dose Rate Brachytherapy Boost for High Risk Adenocarcinoma of the Prostate (PCS VI): Acute Toxicity Results

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of lager fraction size. We have recently shown (PCS5) that high risk prostate cancer patients can safely and effectively be treated with moderate hypofractionated radiation therapy (HF-RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with EBRT and HDR boost (HDRB). We are reporting the acute safety of EBRT+HDRB compared to moderate HF-RT in this phase III Canadian trial. From January 2015-June 2022, 308 high-risk localized PCa patients were randomized to receive either HF-RT or EBRT+HDRB. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). EBRT+HDRB consisted of 46 Gy in 2 Gy per fraction to the pelvis and a 15 Gy in one fraction HDR boost within 3 weeks of EBRT. HF-RT include concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate, and 45 Gy in 1.8 Gy per fraction to the pelvic lymph-nodes. Of the 308 patients, 148 received HF-RT and 144 EBRT+ HDRB. The remainder either withdrew from the study or were treated with standard (2 Gy per fraction) fractionation for technical reasons. In both intention to treat and as treated analysis, using log-Rank, there were more grade 1 or worse (G1+) acute GI and GU events and more G2+ acute GI events in the HF-RT than EBRT+HDRB. As treated analysis the acute G1+ and G2+ GI events were 92 vs 77 (60.1% vs. 53.5%; p < 0.017) and 21 vs 10 (13.7% vs. 6.9%; p = 0.052), respectively for HF-RT and EBRT + HDRB. Similarly, the G1+ acute GU events were 123 vs. 101 (80.4% vs.70.1%; p < 0.001) respectively for HF-RT and EBRT+HDRB. There were only four G3 GI and one G3 GU acute toxicities in both arms. No grade 4 toxicities were reported. This is the first study of EBRT+HDRB compared to moderate HF dose escalated RT in high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Our results demonstrate that both treatment approaches are well-tolerated and that EBRT+HDRB carries less G2+ GI and G1+ GU acute toxicities.

Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial

The low α\β ratio of 1.2 to 2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date, no phase 3 randomized clinical trial has compared moderately HF RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderate HF RT in high-risk PCa in an initially noninferiority-designed phase 3 clinical trial. From February 2012 to March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF RT. All patients received neoadjuvant, concurrent, and long-term adjuvant androgen deprivation therapy. Standard fractionation RT consisted of 76 Gy in 2 Gy per fraction to the prostate, where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT included concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The coprimary endpoints were acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a noninferiority with a 5% absolute margin. Given the lower-than-expected toxicities in both arms, the noninferiority analysis was completely dropped. Of the 329 patients, 164 were randomized to the HF and 165 to the SF arms. In total, there were more grade 1 or worse acute gastrointestinal (GI) events in the HF arm, 102 versus 83 events in the HF and SF arm, respectively (P=.016). This did not remain significant at 8 weeks of follow-up. There were no differences in grade 1 or worse acute GU events in the 2 arms, 105 versus 99 events in the HF and SF arm, respectively (P=.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade 2 or worse delayed GI-related adverse events (hazard ratio, 1.32; 95% CI, 0.62-2.83; P=.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade 2 or higher delayed genitourinary (GU) toxicities (hazard ratio, 0.26; 95% CI, 0.07-0.94; P=.037). There were 3 grade 3 GI and one grade 3 GU delayed toxicities in the HF arm and 3 grade 3 GU and no grade 3 GI toxicities in the SF arm. No grade 4-toxicities were reported. This is the first study of moderate HF dose-escalated RT in exclusively high-risk patients with prostate cancer treated with long-term androgen deprivation therapy and pelvic RT. Although our data were not analyzed as a noninferiority, our results demonstrate that moderately HF RT is well-tolerated, similar to SF RT at 2 years, and could be considered an alternative to SF RT.

Favorable prognosis of patients who received adjuvant androgen deprivation therapy after radiotherapy achieving undetectable levels of prostate-specific antigen in high- or very high-risk prostate cancer.

To determine the prognostic significance of long-term adjuvant androgen deprivation therapy (A-ADT) over 1 year in achieving undetectable levels of prostate-specific antigen (PSA) less than 0.001 ng/mL in prostate cancer patients with high- or very high-risk prostate cancer who underwent radiotherapy (RT). A total of 197 patients with prostate cancer received RT, with a follow-up of ≥12 months. Biochemical failure was defined as PSA ≥nadir + 2 ng/mL after RT. We analyzed clinical outcomes, including survival, failure patterns, and prognostic factors affecting outcomes. Biochemical failure-free survival (BCFFS), clinical failure-free survival, distant metastasis-free survival, cancer-specific survival, and overall survival (OS) rates at 5 years were 91.1%, 95.4%, 96.9%, 99.5%, and 89.1%, respectively. Administration of long-term A-ADT significantly predicted favorable BCFFS (p = 0.027) and OS (p < 0.001) in multivariate analysis. Nadir PSA ≤0.001 ng/mL was an independent prognostic factor for BCFFS (p = 0.006) and OS (p = 0.021). The use of long-term A-ADT significantly affected nadir PSA ≤0.001 ng/mL (p < 0.001). The patients with A-ADT for 1 year or longer had better BCFFS or OS than those for less than 1 year or those without A-ADT (p < 0.001). The best prognosis was demonstrated in patients treated with long-term A-ADT and nadir PSA ≤0.001 ng/mL in BCFFS (p < 0.001). The addition of long-term A-ADT over 1 year to RT demonstrated good treatment outcomes in patients with locally advanced prostate cancer. Achieving a nadir PSA value ≤0.001 ng/mL using combination therapy with RT and A-ADT is a powerful clinical predictor of treatment outcomes.

Ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage therapy may replace long-term adjuvant androgen deprivation

BackgroundThe optimal timing of salvage androgen deprivation therapy (ADT) following definitive radiation therapy for prostate cancer (PCa) is unknown. This study evaluated the efficacy of early initiation of salvage-ADT (S-ADT) based on predetermined timing among patients with unfavorable PCa treated with high-dose intensity-modulated radiation therapy (IMRT).Materials and methodsHigh-risk (HR) and very-high-risk (VHR) PCa patients treated with IMRT at our institution between September 2000 and December 2010 were analyzed retrospectively. Treatment consisted of high-dose IMRT (78 Gy/39 fractions) combined with 6 months of neoadjuvant-ADT (NA-ADT). S-ADT was initiated when prostate-specific antigen levels exceeded 4.0 ng/mL.ResultsIn total, 268 (184 HR and 84 VHR) patients were analyzed. The median follow-up period was 114.4 months. The 10-year overall survival (OS), PCa-specific survival (PCSS), biochemical failure (BF), and clinical failure (CF) rates were 82.8%, 97.1%, 27.3%, and 12.8% among the HR PCa patients and 79.4%, 87.9%, 56.2%, and 26.7% among the VHR PCa patients (p = 0.839, = 0.0377, < 0.001, and < 0.001), respectively. The 10-year cumulative incidence rates of urinary and rectal (grades 2–3) toxicities were 22.6% and 5.8%, respectively. No grade 4 or higher toxicities were observed.ConclusionHigh-dose IMRT combined with short-term NA-ADT resulted in long-term disease-free status, with acceptable morbidity among approximately three-fourths of the HR PCa patients and nearly half of the VHR PCa patients. Moreover, excellent survival outcomes were achieved by the early S-ADT initiation. This approach may be a promising alternative to uniform provision of long-term ADT.

818 - Multi-institutional prospective study comparing oncological outcomes between radical prostatectomy with extended pelvic lymph node dissection versus radiotherapy and longterm adjuvant androgen deprivation therapy for high risk localized prostate cancer

818 - Multi-institutional prospective study comparing oncological outcomes between radical prostatectomy with extended pelvic lymph node dissection versus radiotherapy and longterm adjuvant androgen deprivation therapy for high risk localized prostate cancer

Cessation of long-term adjuvant androgen deprivation therapy after radical prostatectomy: is it feasible?

Adjuvant androgen deprivation therapy is a common treatment option for prostate cancer after radical prostatectomy, especially in Asia. However, no study has investigated the oncological outcome after cessation of long-term adjuvant androgen deprivation therapy with favorable prostate-specific antigen control. Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 56 men with pT2-4N0-1M0 prostate cancer who had received long-term (>2 years) adjuvant androgen deprivation therapy after radical prostatectomy and subsequently stopped it under a condition of continued prostate-specific antigen values <0.1 ng/mL. The oncological outcome was evaluated using biochemical recurrence, defined as two consecutive prostate-specific antigen values ≥0.2 ng/mL, as the primary endpoint. Cox proportional hazards model was used for multivariate analysis. Age at androgen deprivation therapy cessation was dichotomized as <68 years and ≥68 years, based on the most discriminatory cutoff. Median duration of adjuvant androgen deprivation therapy was 70 months. Overall, 13 of 56 (23%) patients developed biochemical recurrence with a median follow-up period of 41 months after androgen deprivation therapy cessation. Multivariate analysis identified age at androgen deprivation therapy cessation <68 years and pN1 as independent predictors of biochemical recurrence. Predisposition of younger age to poorer survival may be related to more frequent testosterone recovery in younger men (73 vs 33%, P = 0.0299). One patient had evidence of clinical metastasis and no one died of prostate cancer. Androgen deprivation therapy cessation would be feasible in most men who received long-term adjuvant androgen deprivation therapy after radical prostatectomy with favorable prostate-specific antigen control. Risk factors of biochemical recurrence after androgen deprivation therapy cessation included younger age at androgen deprivation therapy cessation and pN1.

Effect of Long-Term Hormonal Therapy (vs Short-Term Hormonal Therapy): A Secondary Analysis of Intermediate-Risk Prostate Cancer Patients Treated on NRG Oncology RTOG 9202

NRG Oncology RTOG 9202 was a randomized trial testing long-term adjuvant androgen deprivation (LTAD) versus initial androgen deprivation only (STAD) with external beam radiation therapy (RT) in mostly high-risk and some intermediate-risk prostate cancer patients. RTOG 9408 found an overall survival (OS) advantage in patients with cT1b-T2b disease and prostate-specific antigen (PSA) <20ng/mL, with benefit observed mostly among intermediate-risk patients. It was still unknown whether intermediate-risk patients would experience an additional survival benefit with LTAD; thus, we performed a secondary analysis to explore whether LTAD had any incremental benefit beyond STAD among the intermediate-risk subset of RTOG 9202. The study endpoints were OS, disease-specific survival (DSS), and PSA failure (PSAF). An analysis was performed for all patients enrolled in RTOG 9202 defined as intermediate-risk (cT2 disease, PSA<10ng/mL, and Gleason score=7 or cT2 disease, PSA 10-20ng/mL, and Gleason score <7). This review yielded 133 patients: 74 (STAD) and 59 (LTAD). The Kaplan-Meier method was used to estimate OS; the cumulative incidence approach was used to estimate DSS and PSAF. A 2-sided test was used, with significance level defined to be .05. With over 11years of median follow-up, 39 STAD patients were alive and 33 LTAD patients were alive. There was no difference in OS (10-year estimates, 61% STAD vs 65% LTAD; P=.53), DSS (10-year DSS, 96% vs 97%; P=.72), or PSAF (10-year PSAF, 53% vs 55%; P=.99) between groups. LTAD did not confer a benefit in terms of OS, DSS, or PSAF rates in the intermediate-risk subset in this study. Whereas the subset was relatively small, treatment assignment was randomly applied, and a trend in favor of LTAD would have been of interest. Given the small number of disease-specific deaths observed and lack of benefit with respect to our endpoints, this secondary analysis does not suggest that exploration of longer hormonal therapy is worth testing in the intermediate-risk prostate cancer subset.

Fatigue and other adverse effects in men treated by pelvic radiation and long-term androgen deprivation for locally advanced prostate cancer

Background We compared the development of adverse effects and psychosocial measures from baseline to 36-month follow-up in patients with prostate cancer (T1-3 M0) referred to our department for definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RAD + IMRT) or radiotherapy to the prostatic gland only (RAD), applied with standard adjuvant androgen deprivation (AD) in all patients. Few studies have explored the impact of fatigue on patients’ reported quality of life (QoL) after combined therapy for prostate cancer. Material and methods The 206 consecutive eligible men (RAD + IMRT = 64 and RAD = 142) completed the UCLA-PCI questionnaire for adverse effects at baseline, 12, 24, and 36 months. QoL, anxiety and depression, and fatigue were rated at the same time points. Between-group and longitudinal within-group changes at different time points were reported. At 36 months variables associated with fatigue were analyzed with regression analyses. Results Our main novel finding is the long-term high level of fatigue and high prevalence of chronic fatigue, affecting patients receiving radiotherapy combined with long-term AD. Except for urinary bother in the RAD + IMRT group all functions and the other bothers mean scores were significantly worse at 36 months compared to baseline. In multivariable analyses only physical QoL remained significantly associated with fatigue at 36-months follow-up. Conclusions Fatigue and impaired QoL in patients considered to curative irradiation with long-term AD should be addressed when counseling men to combined treatment.

Progress in the treatment of localized prostate cancer with external beam irradiation

The efficacy of the conventional 2D technique of radiation treatment planning and delivery Is limited by toxicity of normal tissue surrounding the target, such that the radiation dose that can be safely delivered to the prostate by external beam radiotherapy cannot exceed 70-72 Gy. Recent technological advances In radiation treatment planning and delivery have allowed higher doses of radiation (>72 Gy) to be safely delivered to the prostate with corresponding Improved outcomes. Over the past decades, high-energy (≥4MV) linear accelerators have gradually replaced Cobalt machines In external-beam radiation therapy delivery. 2D radiation therapy treatment systems have changed to 3D conformal radiation therapy and Intensity-modulated radiation therapy computed tomography-based systems, allowing tighter tumor margins and decreasing normal tissue toxicities. By switching to computed tomography-based planning, 3D-conformal radiation therapy provides better relative conformality of dose than conventional external beam irradiation therapy. Intensity-modulated radiation therapy has further refined dose conformality by spreading the low-dose region to a larger volume. Parallel with the development and implementation of 3D-conformal radiation therapy and intensity-modulated radiation therapy, improved precision of both target definition and treatment verification can be accomplished by Image guidance systems to correct for interfraction and Intrafraction movement of the prostate In real time. However, the potential long-term risks of larger volumes of normal tissues receiving low doses of radiation In Intensity-modulated radiation therapy are unknown. Particle beam radiation therapy (PBRT) offers unique dose distributions and characteristics with higher relative biological effect and linear energy transfer. PBRT Is believed to be more effective In controlling slowly proliferating tumors such as prostate carcinoma. However, the availability of PBRT Is limited and the development of economically operable particle beam radiation therapy facilities In the USA Is still In progress. Finally, the addition of hormonal therapy to radiation therapy has been shown to Improve outcome In selected patients. Androgen deprivation causes cytoreduction of the prostate cancer (smaller volume treated to high doses), better local control and disease-free survival. Long-term adjuvant androgen deprivation has also been shown to Improve overall survival, especially In more advanced tumors.

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The role of surgery in high‐risk localised prostate cancer

• The optimal management of high-risk localised prostate cancer is a major challenge for urologists and oncologists. It is clear that multimodal therapy including radical local treatment is needed in these men to achieve the best outcomes. • External beam radiotherapy (EBRT) is an essential component of therapy either as a primary or adjuvant treatment. However, the role of radical prostatectomy (RP) is more controversial. Both methods are currently valid therapy options. • There have been many individual studies of EBRT and RP in high-risk disease, but no good quality large prospective randomized trials. • In EBRT, combination with neoadjuvant plus long-term adjuvant androgen-deprivation therapy (ADT) has been conclusively shown to improve outcomes and is widely considered the standard of care. • However, the role of RP has achieved recent prominence with several important studies. Published data from prospective randomized trials in patients after RP have shown that in men with adverse pathological features at surgery, the addition of adjuvant RT improves biochemical-free and progression-free survival. • More recently, studies from large-volume centres comparing EBRT and RP have provided intriguing suggestions of better outcomes with RP as the primary treatment. • An important question therefore, is which of the two methods provides the best outcome in men with localised high-risk disease. Crucially, does the combination of RP and selective adjuvant EBRT provide clinically significant better outcomes compared with EBRT alone? • In this review we discuss the current evidence for the role of RP for high-risk localised prostate cancer and define the parameters and urgent need for a prospective trial to test the role of surgery for this group of patients.

The Effect of Androgen Deprivation Therapy on Fasting Serum Lipid and Glucose Parameters

Although prostate cancer specific mortality is decreasing, there is little effect on overall mortality in this population, suggesting the possibility of an increased risk of death from nonprostate cancer related causes. Androgen deprivation therapy could adversely affect cardiovascular health. We investigated changes in lipid and glucose during androgen deprivation therapy. We performed an exploratory analysis of pooled data from 3 prospective clinical trials aimed at achieving medical castration by comparing the gonadotropin releasing hormone antagonist abarelix, the gonadotropin releasing hormone agonist leuprolide acetate and leuprolide acetate plus the antiandrogen bicalutamide. Most patients were treated in the neoadjuvant setting or because of biochemical recurrence. Fasting serum lipid, glucose and hemoglobin A1C were determined in 1,102 men at baseline, and on treatment days 85 and 169. In the current study men were categorized into 3 treatment groups according to the type of androgen deprivation therapy, that is leuprolide acetate, leuprolide acetate plus bicalutamide or abarelix, and statin therapy. Significant increases in total cholesterol, triglyceride and high density lipoprotein-cholesterol were observed in patients on leuprolide acetate or abarelix but not in patients on leuprolide acetate plus bicalutamide. Consistent changes in low density lipoprotein-cholesterol were not detected. Increased total cholesterol was usually due to an increase in high density lipoprotein-cholesterol. Hemoglobin A1C increased from baseline to day 85 only and there were no significant changes in fasting glucose measurements. The type of androgen deprivation therapy did not affect these parameters. Short-term androgen deprivation therapy affects serum lipid and hemoglobin A1C independent of statin therapy.

Testosterone and erectile function recovery after radiotherapy and long‐term androgen deprivation with luteinizing hormone‐releasing hormone agonists

To study the recovery of testosterone levels and erectile function in men who received radiotherapy plus long-term adjuvant androgen deprivation (LTAD) with luteinizing hormone-releasing hormone (LHRH) agonists. From April 2000 to July 2001, men who had completed prostate radiotherapy with > or = 2 years of LTAD, and had their last LHRH agonist injection at least 6 months before, were invited to participate. At study entry, the men completed the International Index of Erectile Function (IIEF), and their serum total testosterone (TT), prostate-specific antigen, LH, follicle-stimulating hormone, haemoglobin, and body mass were measured. This assessment was repeated at 1 year. In all, 20 men were recruited, with a mean (range) age of 70 (55-81) years. Defining a normal TT level as > or = 8.0 nmol/L, the median time to a normal level was 2.3 years (95% confidence interval (CI), 1.9-4.2). The median duration of castrate TT levels was 8 months (95% CI, 6.2-14.9). LH recovered before TT, suggesting that the rate-limiting step in the recovery of TT may be at the testicular level. The median time to recovery of normal LH levels was 3.8 months, compared to 8.0 months to reach supracastrate TT levels, and 2.3 years to reach normal TT levels. Age and the LH/TT ratio were associated with the time to recovery of both supracastrate and normal levels of TT. The IIEF was completed by 17 men; there were no significant changes in the scores in any domain of the IIEF during the study. Most men recover supracastrate testosterone levels after LTAD and external beam radiotherapy, but recovery of 'normal' testosterone levels is slow. Few men recover potency and sexual desire. The patients age and LH/TT ratio may be predictive of the time to recovery of both supracastrate and normal testosterone levels.

Technological advances in radiotherapy for the treatment of localised prostate cancer

There is good evidence that radiation dose escalation in localised prostate cancer is associated with increased cell kill. The traditional two-dimensional (2D) technique of treatment planning and delivery is limited by normal tissue toxicity, such that the dose that can be safely delivered to the prostate by external beam radiotherapy is 65–70 Gy. Several technological advances over the last 20 years have enhanced the precision of external beam radiotherapy (EBRT), and have resulted in improved outcomes. The three-dimensional conformal radiotherapy (3D-CRT) approach reduces the dose-limiting late side-effect of proctitis and has allowed for dose escalation to the whole prostate to 78 Gy. More recently, intensity modulated radiotherapy (IMRT), an advanced form of conformal therapy, has resulted in reduced rectal toxicity when using doses greater than 80 Gy. In addition, IMRT can potentially escalate the dose to specific parts of the prostate where there are resistant subpopulations of tumour clonogens, or can be used to extend the high-dose region to pelvic lymph nodes. The addition of androgen deprivation to conventional radiotherapy has an impact on survival and local control. Initial hormone therapy causes cytoreduction of the prostate cancer allowing for a reduction in radiotherapy volume as well as an additive effect on cell kill. Long-term adjuvant androgen deprivation has been shown to improve overall survival in more advanced tumours. Prostate brachytherapy is now a recognised treatment for those with low-risk disease. It achieves similar long-term outcome to other treatment modalities. Brachytherapy can be used as monotherapy for localised disease, or as boost treatment following conventional EBRT for locally advanced disease. New techniques are available to improve the precision of both target definition and treatment verification. This so-called image-guided radiotherapy will help to enhance the accuracy of dose delivery by correcting both for inter-fraction positional variation and for intra-fraction movement of the prostate in real-time and will allow for tighter tumour margins and avoidance of normal tissues, thereby enhancing the safety of treatment.

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU, Radiation Therapy Oncology Group, Fox Chase Cancer Center and Radiation

Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P = .73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P = .044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P = .037), the cause of which is not clear. The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.

BICALUTAMIDE 150 MG IN ADDITION TO STANDARD CARE IN PATIENTS WITH LOCALIZED OR LOCALLY ADVANCED PROSTATE CANCER: RESULTS FROM THE SECOND ANALYSIS OF THE EARLY PROSTATE CANCER PROGRAM AT MEDIAN FOLLOWUP OF 5.4 YEARS

We evaluated the efficacy and tolerability of 150 mg bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer. The bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b-T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival. At median 5.4 years of followup (21.6% progression events) bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of underlying therapy. Overall survival was similar in the bicalutamide and placebo groups, across the program and in each trial. Among watchful waiting patients survival appeared to be improved with bicalutamide in those with locally advanced disease, whereas survival appeared to be reduced with bicalutamide in those with localized disease. The most common adverse events with bicalutamide were gynecomastia and breast pain. Other adverse events occurred with a similarly low incidence in the 2 treatment groups. This analysis confirms that bicalutamide provides benefit in patients with locally advanced disease. The current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localized disease, is not appropriate.

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU, Radiation Therapy Oncology Group, Fox Chase Cancer Center and Radiation

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU, Radiation Therapy Oncology Group, Fox Chase Cancer Center and Radiation

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate

Purpose: To determine the potential advantage of androgen ablation following standard external-beam radiation therapy in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node positive) carcinoma of the prostate. Methods and Materials: In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients were accrued to the study of which 945 remain analyzable: 477 on the adjuvant hormone arm (Arm I); and 468 on the radiation only arm (Arm II) with hormones initiated at relapse. The initial results were reported in the Journal of Clinical Oncology in 1997. Results: With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23% for Arm I and 37% for Arm II ( p < 0.0001). Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27% and 37% in Arm II ( p < 0.0001). Disease-free survival (NED survival) and NED survival with PSA of 1.5 ng/mL (bNED) or less were both statistically significant in favor of the immediate hormone arm (both p < 0.0001). Cause-specific failure was not statistically different with a cause-specific failure of 16% for Arm I and 21% in Arm II ( p = 0.23). Overall survival was likewise not statistically different between two arms, with a 49% overall survival at 8 years in Arm I and 47% in Arm II ( p = 0.36). Subset analysis of centrally reviewed Gleason 8–10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute ( p = 0.036) and cause-specific survival ( p = 0.019). Conclusions: Use of long-term adjuvant androgen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control, freedom from distant metastasis, and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate.