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

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

Photoinduced electron-transfer chemistry of the bielectrophoric N-phthaloyl derivatives of the amino acids tyrosine, histidine and tryptophan

The photochemistry of phthalimide derivatives of the electron-rich amino acids tyrosine, histidine and tryptophan 8–10 was studied with respect to photoinduced electron-transfer (PET) induced decarboxylation and Norrish II bond cleavage. Whereas exclusive photodecarboxylation of the tyrosine substrate 8 was observed, the histidine compound 9 resulted in a mixture of histamine and preferential Norrish cleavage. The tryptophan derivative 10 is photochemically inert and shows preferential decarboxylation only when induced by intermolecular PET

A New Directing Mode for Singlet Oxygen Ene Reactions: The Vinylogous Gem Effect Enables a ¹O₂ Domino Ene/[4 + 2] Process

The singlet oxygen reactions of 4-methyl-2,4-hexadienoates E,E- and E,Z-<b>4</b> proceed in a highly mode selective and regioselective domino process. The initial product is the allylic hydroperoxide <b>5</b> directed by a vinylogous gem effect. The subsequent ¹O₂ [4 + 2] cycloaddition delivers a 3:2 diastereoisomeric mixture of 1,2-dioxanes <b>8</b> in a one-pot process. The identical protocol delivers from the more reactive α-methylated substrates E,E-<b>10</b> and E,Z-<b>10</b> with excellent primary regioselectivity the 1,2-dioxane <b>13</b>

Singlet oxygen and natural substrates: functional polyunsaturated models for the photooxidative degradation of carotenoids

The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized

ChemInform Abstract: Singlet Oxygen and Natural Substrates: Functional Polyunsaturated Models for the Photooxidative Degradation of Carotenoids

The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized

Ene-Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The Vinylogous Gem Effect and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds 1b-d were compared with those of the geminal (gem) selectivity model ethyl tiglate (1a). The kinetic cis effect is k(E)/k(Z) = 5.2 for the tiglate/angelate system 1a/1a' without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes 1e-g. A vinylogous gem effect was observed for the gamma,delta-dimethylated and alpha,gamma,delta-trimethylated substrates 1h and 1i, respectively. The corresponding phenylated substrates 1j-1 showed similar mode selectivity, as monomethylated 1j exhibited exclusively [4 + 2] reactivity while the tandem products 12 and 14 were isolated from the di- and trimethylated substrates 1k and 1l, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes 19 and 20 in an ene-diene transmissive cycloaddition sequence. These products were reduced to give alcohols (16, 17, and 18) or furans (24 and 25), respectively, or treated with titanium(IV) alkoxides to give the epoxy alcohols 26 and 27. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete