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

Can differentiation adequately account for the influence of word type on episodic recognition memory?

In episodic recognition memory, differentiation is the assumption that a study item's pre-existing memory trace is updated when additional study for that item is provided. The differentiation models commonly suppose that episodic memory encoding conforms to this process. Although these models have received considerable support within the literature, results inconsistent with their predictions have also been found. The present paper examined conflicting findings that resulted from study list strength manipulations with rhyming word stimuli and semantically related stimuli. As part of the investigation into this discrepancy, 79 university students participated in a computer-based recognition memory task. In this task, word categories of varying length (short vs. long) and word type (rhyming vs. taxonomic) were presented either five times or once within a mixed study list. Following study, an old-new response paradigm was used to examine recognition memory performance. Results from both the rhyming and taxonomic category stimuli were largely consistent with the previous findings in the literature, indicating that word type does appear to influence recognition memory, even within a mixed study list. These findings are interpreted primarily in terms of word type similarity predictions made by one of the differentiation models. Other possible explanations are also discussed

Maintenance rehearsal: the key to the role attention plays in storage and forgetting

We examined associative and item recognition using the maintenance rehearsal paradigm. Our intent was to control for mnemonic strategies; to produce a low, graded level of learning; and to provide evidence of the role of attention in long-term memory. An advantage for low-frequency words emerged in both associative and item recognition at very low levels of learning. This early emergence casts doubt on explanations based on the traditional concept of recollection. A comparison of false alarms supports a role for item information or the joint use of cues but not familiarity in producing associative false alarms. We may also have found a way to measure the amount of attention being paid to a to-be-learned item or pair, independently of memory performance on the attended item. This result may be an important step in determining whether coherent theories about the role of attention in long- and short-term memory can be created

Measuring mental time travel: Is the hippocampus really critical for episodic memory and episodic foresight?

Mental time travel is an adaptive capacity that enables humans to engage in deliberate, prudent action on the basis of remembering past episodes (episodic memory) and simulating future scenarios (episodic foresight). This capacity has become a popular and rapidly growing topic of interdisciplinary research. Perhaps the most influential and frequently tested neuroscientific hypothesis in this domain is that the hippocampus is a hub in a critical neural network for mental time travel, support for which is now commonly assumed by most researchers in the area. In light of recent findings revealing limitations with existing measures of episodic foresight, we critically evaluate the available evidence for this hypothesis and find that it is inconclusive. We suggest that this is due in significant part to the exclusive and widespread reliance on noisy verbal measures and discuss this case as an example of a more general issue pertaining to the measurement of episodic foresight. Accordingly, we suggest that an essential focus of future research should concern the development of objective measures that capture capacity differences by requiring people to put foresight not just into words, but into action

Recognition in context: implications for trade mark law

Context effects in recognition have played a major role in evaluating theories of recognition. Understanding how context impacts recognition is also important for making sound trade mark law. Consumers attempting to discriminate between the brand they are looking for and a look-alike product often have to differentiate products which share a great deal of common context: positioning on the supermarket shelf, the type of store, aspects of the packaging, or brand claims. Trade mark and related laws aim to protect brands and reduce consumer confusion, but courts assessing allegations of trade mark infringement often lack careful empirical evidence concerning the impact of brand and context similarity, and, in the absence of such evidence, make assumptions about how consumers respond to brands that downplay the importance of context and focus on the similarity of registered marks. The experiments reported in this paper aimed to test certain common assumptions in trade mark law, providing evidence that shared context can cause mistakes even where brand similarity is low

Using maintenance rehearsal to explore recognition memory

We examined associative and item recognition using the maintenance rehearsal paradigm. Our intent was to control for mnemonic strategies; to produce a low, graded level of learning; and to provide evidence of the role of attention in long-term memory. An advantage for low-frequency words emerged in both associative and item recognition at very low levels of learning. This early emergence casts doubt on explanations based on the traditional concept of recollection. A comparison of false alarms supports a role for item information or the joint use of cues but not familiarity in producing associative false alarms. We may also have found a way to measure the amount of attention being paid to a to-be-learned item or pair, independently of memory performance on the attended item. This result may be an important step in determining whether coherent theories about the role of attention in long- and short-term memory can be created. © 2010 American Psychological Association