Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury

<div><p>Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N¹-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H₂O₂ and aminopropanal, significantly diminished the severity of cisplatin AKI. <i>In vitro</i> studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.</p></div

Overexpression of SSAT in cultured cells: impact on ERSR and apoptosis.

<p>A & B) Treatment of HEK-SSAT-Trex cells with tetracycline led to the induction of SSAT a significant elevation in Put and reductions in Spd and Spm levels. C) Western blot analyses indicate that the induction of SSAT leads to a reduction in hypusinated-eIF5A levels, a time-dependent transient increase in p-eIF2α, BiP and CHOP levels. Increased activated caspase3 levels were also detected in samples from 48 to 72 hours post Tetracycline-induction of SSAT expression. The results are representative of 3 independent experiments (* Denotes <i>P</i><0.01).</p

The impact of neutralization of toxic products of polyamine degradation on the induction of ERSR and onset of apoptosis.

<p>A) The expression levels of BiP and CHOP increased in the kidneys of cisplatin-treated mice compared to saline treated animals. The expression levels of BiP and CHOP were reduced in the kidneys of cisplatin-treated mice that were subjected to daily treatment with PEG-Cat/N-2-MPG or PLZ. The results are representative of 3 independent experiments. B) The activation of caspase 3 (arrows) was more robust in the kidneys of Wt cisplatin-treated mice receiving vehicle compared to the mice treated with cisplatin and subjected to daily PEG-Cat/N-2-MPG or PLZ treatment.</p

Effect of cisplatin treatment on renal function and structure and the expression of polyamine catabolic enzymes.

<p>A & B) Administration of cisplatin (20mg/kg) led to significantly increased serum creatinine levels tubular injury ranging from mild (48 hours) to severe (96 hours) post-treatment (vacuolization, small arrow head; cast, small arrows; sloughed cells and damaged tubules, large arrows). C) Expression of SSAT and SMOX mRNA levels increase in kidneys of mice treated with cisplatin.</p

Depiction of polyamine synthetic and catabolic reactions.

<p>This schematic indicates that the oxidation of acetylated polyamines and via APAOX or SMOX, respectively, leads to the generation of cytotoxic molecules (H₂O₂ and aminoaldehydes).</p

The consequence of SSAT and SMOX ablation on the induction of ERSR and onset of apoptosis.

<p>The effect of modulation of polyamine catabolism on the activation of ERSR and onset of apoptosis in cisplatin AKI was examined. A) The levels of BiP and CHOP were similar in the control samples from all 3 genotypes. The expression of BiP and CHOP increased in all three genotypes after cisplatin treatment; however, the BiP and CHOP expression levels were reduced in cisplatin treated SMOX-KO and SSAT-KO mice compared to their cisplatin-treated Wt counterparts. The results are representative of 3 independent experiments. B) The levels of activated caspase 3 (arrows) were also significantly elevated in the kidneys of Wt compared to SSAT-KO and SMOX-KO mice.</p

Effect of SSAT and SMOX ablation on cisplatin AKI induced changes in ODC, SSAT and polyamine levels.

<p>A) The activity of ODC is approximately 2-fold lower in saline treated SSAT-KO and SMOX-KO mice compared to their Wt littermates (p<0.05); however, the reduction in ODC activity in all 3 groups subsequent to cisplatin treatment is of a similar magnitude and significant. (*Denotes significantly higher enzymatic activity in control vs. cisplatin-treated animals). B) Renal SSAT activity is similar in saline treated Wt and SMOX-KO mice. The SSAT activity is significantly elevated in Wt mice treated with cisplatin compared to those treated with saline. (*Denotes significantly higher enzymatic activity in cisplatin-treated vs. control animals. ⁺Denotes a significant increase in cisplatin-treated Wt compared to similarly treated SMOX-KO and SSAT-KO mice. ^#Denotes significant increase in cisplatin-treated SMOX-KO to SSAT-KO mice). C) SMOX protein levels are elevated in the kidneys of cisplatin-treated Wt animals compared to saline treated and cisplatin treated SSAT-KO mice. D) Examination of tissue polyamine levels reveals that the kidney Put content increases significantly in Wt but not SMOX- and SSAT-KO mice after cisplatin treatment. The Spd content of the kidneys only marginally increases in Wt and SSAT-KO mice after cisplatin treatment. Examination of Spm levels indicates that their reduction is significantly greater in the Wt mice than SMOX-KO and SSAT-KO animals. (*Denotes significantly increased content in cisplatin-treated vs saline-treated animals of the same genotype. ⁺Denotes a significant decrease in tissue content in cisplatin-treated animals compared to saline-treated animals of the same genotype. ^#Denotes a significant decrease in tissue content compared to saline-treated Wt mice).</p