Crook J, Ludgate C, Malone S, Lim J, Perry G, Eapen L, Bowen J, Robertson S, Lockwood GReport of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 60(1): 15-23

The Princess Margaret Hospital, Toronto, Ontario, Canada
International Journal of Radiation OncologyBiologyPhysics (Impact Factor: 4.26). 10/2004; 60(1):15-23. DOI: 10.1016/j.ijrobp.2004.02.022
Source: PubMed


To evaluate the effect of 3 months vs. 8 months of neoadjuvant hormonal therapy before conventional dose radiotherapy (RT) on disease-free survival using prostate-specific antigen PSA and biopsies as end points for clinically localized prostate cancer.
Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before conventional-dose RT (66 Gy) at four participating centers. The median patient age was 72 years (range, 50-84 years). The stage distribution was 17% T1c, 35% T2a, 34% T2b-T2c, 13% T3-T4. The Gleason score (GS) was < or =6 in 51%, 7 in 38%, and 8-10 in 11%. The median baseline PSA level was 9.7 ng/mL (range, 1.3-189 ng/mL). Of the 378 men, 26% were low risk (Stage T1c-T2a, GS < or =6, PSA <10 ng/mL), 43% were intermediate risk (Stage T2b or GS 7 or PSA 10-20 ng/mL), and 31% were high risk (Stage T3 or GS 8-10 or PSA >20 ng/mL). The two arms were balanced in terms of age, GS, T stage, risk group, and presenting PSA level. The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation.
The 8-month arm achieved a lower PSA level before starting RT (0.37 vs. 0.74 ng/mL, p < or =0.001) and had a greater downsizing of the prostate (mean volume 26.6 cm(3) vs. 30.5 cm(3), p < or =0.001). However, the actuarial freedom from failure rate (biochemical by American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. 8-month arms at 3 years was 66% vs. 68% and by 5 years was 61% vs. 62%, respectively (p = 0.36). No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical, 22.2% vs. 22.3%; local, 10.2% vs. 6.5%; and distant, 3.4% vs. 4.4% (p = 0.61). Two-year post-RT biopsies were done in 57% (n = 205). Negative biopsies were obtained in 68% of the 3-month and 77% of the 8-month patients; 18% and 14% had indeterminate biopsies and 14% and 9% were positive for residual cancer (p = 0.34) in the two arms, respectively. The median PSA level for nonfailing patients was 0.50 ng/mL in both the 3-months and 8-month arms. A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs. 52%) but did not achieve statistical significance.
A longer period of neoadjuvant hormonal therapy before standard-dose RT does not appear to confer a benefit in terms of disease-free survival or to alter failure patterns. Failure was delayed in the 8-month arm, but this advantage was lost by 5 years of follow-up. A suggestion of benefit was noted with a longer period of hormonal therapy for high-risk patients.

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    • "We added another 18 articles from reviews, for 222 full-text articles assessed for eligibility. Finally, after excluding 161 articles, 61 reports assessing results of 27 RCTs (Zagars et al, 1988; Pilepich et al, 1995; Shipley et al, 1995; Pollack et al, 1996; Bolla et al, 1997; Lawton et al, 1997; Pilepich et al, 1997; Granfors et al, 1998; Nguyen et al, 1998; Pollack et al, 2000; Storey et al, 2000; Lawton et al, 2001; Pilepich et al, 2001; Bolla et al, 2002; Pollack et al, 2002; Hanks et al, 2003; Lamb et al, 2003; Yeoh et al, 2003; Ataman et al, 2004; Beckendorf et al, 2004; Crook et al, 2004; D&apos;Amico et al, 2004; Laverdiere et al, 2004; Christie et al, 2005; Dearnaley et al, 2005; Denham et al, 2005; Lawton et al, 2005; Lukka et al, 2005; Peeters et al, 2005; Pilepich et al, 2005; Sathya et al, 2005; Zietman et al, 2005; Granfors et al, 2006; Peeters et al, 2006; Yeoh et al, 2006; Dearnaley et al, 2007; Al-Mamgani et al, 2008; D'Amico et al, 2008; Horwitz et al, 2008; Kuban et al, 2008; Roach et al, 2008; Bolla et al, 2009; Crook et al, 2009; Marzi et al, 2009; Strigari et al, 2009; Norkus et al, 2009a, 2009b; Alexander et al, 2010; Arcangeli et al, 2010; Bolla et al, 2010; Heemsbergen et al, 2010; Zietman et al, 2010; Al-Mamgani et al, 2011; Arcangeli et al, 2011; Armstrong et al, 2011; Beckendorf et al, 2011; Denham et al, 2011; Jones et al, 2011; Yeoh et al, 2011; Arcangeli et al, 2012; Dearnaley et al, 2012) were used in the network meta-analysis, for 13 364 patients with local or locally advanced prostate cancer randomly assigned to receive one of the seven RT regimens examined (Figures 1 and 2). The median age of patients ranged from 65 to 75 years and median follow-up ranged from 1 to 14.5 years, mostly were from 5 to 10 years. "
    Z Zhu · J Zhang · Y Liu · M Chen · P Guo · K Li
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    ABSTRACT: Background: Many radiation regimens for treating prostate cancer have been used over the years, but which regimen is optimal for localised or locally advanced prostate cancer lacks consensus. We performed a network meta-analysis to identify the optimal radiation regimen. Methods: We systematically reviewed data from 27 randomised controlled trials and could group seven radiation regimens as follows: low- and high-dose radiation therapy (LDRT and HDRT), LDRT+ short- or long-term androgen deprivation therapy (LDRT+SADT and LDRT+LADT), HDRT+SADT, hypofractionated radiotherapy (HFRT), and HFRT+SADT. The main outcomes were overall mortality (OM), prostate-specific antigen (PSA) failure, cancer-specific mortality, and adverse events. Results: For the network meta-analysis of 27 trials, LDRT+LADT and LDRT+SADT were associated with decreased risk of OM as compared with LDRT alone as was LDRT+LADT compared with HDRT. Apart from HFRT, all other treatments were associated with decreased risk of PSA failure as compared with LDRT. HFRT+SADT was associated with decreased risk of cancer-specific mortality as compared with HFRT, LDRT+SADT, HDRT, and LDRT. Conclusions: HFRT+SADT therapy might be the most efficacious treatment but with worst toxicity for localised or locally advanced prostate cancer, and HDRT showed excellent efficacy but more adverse events.
    Full-text · Article · Apr 2014 · British Journal of Cancer
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    • "Unfortunately local progression is difficult to diagnose reliably by digital examination and the magnitude of the reductions found is open to doubt. In RTOG 94.06 and two Canadian randomised controlled trials where prostatic biopsies were planned to occur 24 months after radiation, persistent cancer was found in as many as 65% of men treated by radiation alone, 14–28% in men treated with 3 or 4 month NAS and 5–9% of men treated with 8 or 9 month NAS [18] [19] [20]. Had biopsy and MRI data been available the frequency and timing of our LP estimates could have been more reliable. "
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    ABSTRACT: Purpose: In the TROG 96.01 trial 6 month neo-adjuvant androgen suppression (NAS) and radiotherapy (RT) for locally advanced prostate cancer prevented distant progressions (DPs) when compared to RT alone, but 3 months did not. We ask why? Methods: Between 1996 and 2000, 802 men with T2-4 N0 M0 prostate cancers received RT alone (0 month NAS) to 66 Gy, 3 months or 6 months NAS before RT. Interval hazards and cumulative incidences of DP were compared using competing risks methodology. Results: In the first 4 follow-up years 39, 40 and 26 DPs were diagnosed in subjects treated with 0, 3 and 6 month NAS, respectively. Compared with 0 month, significant reductions in PSA doubling time in subjects with DP occurred following 3 month NAS (p=0.01), but a significant reduction (p=0.01) and a near significant delay in DPs (p=0.06) occurred after 6 month NAS. Subsequently 25, 20 and 11 DPs occurred in the three trial arms. After early secondary therapy for PSA or local progression 34, 19 and 12 DPs were diagnosed after median delays of almost 4 years. Conclusions: The data are consistent with the failure of 3 month NAS to prevent the progression of sub-clinical metastatic deposits already present before treatment.
    Full-text · Article · Apr 2013 · Radiotherapy and Oncology
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    • "Logically, the duration of ADT has since become the focus in a number of studies. A Canadian study which included T1c-T4 tumors, compared 3 and 8 months neo-adjuvant ADT and showed improvements in cause-specific survival in a high risk sub-set with longer ADT durations, according to a recent oral update of a prior publication [16]. The RTOG 92–02 study looked at more prolonged ADT, comparing 4 months with 24 months. "
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    ABSTRACT: To assess whether an expanded (five level) risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT) with external beam radiotherapy (EBRT). Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED) with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL), both with and without adjuvant ADT. The median follow-up was 5 years. There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant) and 72% and 58% respectively for the high intermediate group (p = 0.002). There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.
    Full-text · Article · Feb 2008 · Radiation Oncology
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