key: cord-0972610-it4a3frb
authors: Araújo, Natália; Costa, Adriana; Lopes-Conceição, Luisa; Ferreira, Augusto; Carneiro, Filipa; Oliveira, Jorge; Braga, Isaac; Morais, Samantha; Pacheco-Figueiredo, Luís; Ruano, Luis; Cruz, Vítor Tedim; Pereira, Susana; Lunet, Nuno
title: Androgen deprivation therapy and cognitive decline in the NEON-PC prospective study, during the COVID-19 pandemic.
date: 2022-03-07
journal: ESMO Open
DOI: 10.1016/j.esmoop.2022.100448
sha: 47db6f320f59c2eb834e07425ae5a8ce9f46ed7d
doc_id: 972610
cord_uid: it4a3frb

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with cognitive decline, but results are conflicting. This study describes changes in cognitive performance in patients with prostate cancer, according to ADT, during the first year after prostate cancer diagnosis. METHODS: Prostate cancer patients treated at the Portuguese Institute of Oncology of Porto (n=366) were evaluated with the Montreal Cognitive Assessment (MoCA), before treatment and after one year. All baseline evaluations were performed before the COVID-19 pandemic and 69.7% of the one-year assessments were completed after the first lockdown. Cognitive decline was defined as the decrease in MoCA from baseline to the one-year evaluation below 1.5 standard deviations of the distribution of changes in the whole cohort. Participants scoring below age- and education-specific normative reference values in the MoCA were considered to have cognitive impairment. Age- and education-adjusted odds ratios (aOR) were computed for the association between ADT and cognitive outcomes. RESULTS: Mean MoCA scores increased from baseline to the one-year evaluation (22.3 vs. 22.8, p<0.001). Cognitive decline was more frequent in the ADT group, and even more after the onset of the COVID-19 pandemic (aOR 6.81 vs. 1.93, p for interaction=0.233). The one-year cumulative incidence of cognitive impairment was 6.9% (9.1% before and 3.7% after the pandemic onset), which was higher among patients receiving ADT, but only after the pandemic (aOR 5.53 vs. 0.49, p for interaction=0.044). CONCLUSIONS: ADT was associated with worse cognitive performance of patients with prostate cancer, mostly among those evaluated after the first COVID-19 lockdown.

With nearly five million five-year prevalent cases estimated in 2020, patients with prostate cancer represent 80

Participants were considered to have cognitive impairment when scoring in the MoCA, below age-and 151 education-normative reference values (1.5 SD below the mean 21, 22 ). Among participants with no cognitive 152 impairment at baseline, those presenting cognitive impairment at the one-year evaluation were considered 153 to have incident cognitive impairment. 154

The incidence of cognitive impairment and cognitive decline was compared between the ADT group and the 155 non-ADT group using multivariate logistic regression to estimate odds ratios (OR) and the corresponding 95% 156 confidence intervals (95%CI). The ADT group included patients treated with ADT only, those treated with 157 radiotherapy (with or without brachytherapy) and ADT, those treated with ADT and chemotherapy, and those 158 with persistent disease after radical prostatectomy and/or radiotherapy, treated with ADT. Stratified analyses 159

were conducted according to the moment of the one-year follow-up, and interaction terms computed: before 160 vs. after the onset of the pandemic. 161

Participants with the one-year evaluation performed after the pandemic onset were more educated (55.7% 163 vs. 50.6% had more than 5 years of education, p=0.016) but were similar regarding age and lifestyles. Nearly 164 half never smoked and were practicing the recommended amount of physical activity, nearly 30% had a BMI 165 lower than 25 kg/m 2 and half had hypertension (Table 2) . 166

Mean MoCA scores increased from baseline to the one-year evaluation (mean, SD: 22.3, 3.7 vs. 22.8, 3.8, 167 respectively; p<0.001), but this variation, when the one-year evaluation was performed after the onset of 168 COVID-19 pandemic, was not statistically significant. 169 Table 3 presents the mean difference in MoCA t-scores from baseline to the one-year evaluation according to 170 prostate cancer treatment. Only the group treated with ADT and chemotherapy, and those who underwent 171 radical prostatectomy (without adjuvant radiotherapy) had a statistically significant increase in mean t-scores 172 over time [mean difference of MoCA t-score at one-year minus MoCA t-score at baseline (95%CI): 7.59 (0.52, 173 14.67) and 3.73 (1.10, 6.37), respectively]. Participants treated with ADT only had a non-statistically significant 174 decrease and the remaining treatment groups had non-statistically significant increases. The increase in scores 175 was less pronounced after the COVID-19 pandemic. 176

At baseline, 47 participants had cognitive impairment and of these, 51.6% scored within the normal MoCA 177 range at the one-year evaluation. Patients with cognitive decline presented a variation in MoCA scores that 178 ranged from -9 to -4 points. 179 Table 4 presents the percentage of participants with cognitive decline and with incident cognitive impairment 180 at the one-year evaluation according to treatments received. None of the patients treated with prostatectomy 181 or with radiotherapy only had cognitive decline. Patients with ADT as part of their treatments presented 182 cognitive decline more often (range: 7.8% -16.0%). There were 22 incident cases of cognitive impairment 183 corresponding to a one-year cumulative incidence of cognitive impairment of 6.9% (95%CI: 4.3%, 10.2%), 184 which was higher after the COVID-19 pandemic (9.1% vs. 3.7%, p=0.057) . Patients who received radiotherapy 185 cognitive impairment (15.4%), followed by those treated with radiotherapy combined with long duration ADT 187 (13.1%), and those treated with ADT for incident prostate cancer only (10.0%). None of the patients who 188 received ADT and chemotherapy had incident cognitive impairment at one-year. 189 A higher educational level (more than 12 years) was associated with cognitive decline 7.46) ]. Patients who underwent treatments including ADT had higher odds of cognitive 191 decline compared with patients who were not treated with ADT 192 95%CI) Overall, cognitive performance increased from baseline to the one-year evaluation. Patients treated with ADT 202 were more likely to have cognitive decline after one year of follow-up. The incidence of cognitive impairment 203 was almost 7% and it was higher in patients treated with ADT, alone or with other treatments, but this effect 204 was only observed when the one-year assessment was conducted after the In the current study, mean MoCA scores increased over time, which was also observed in women with breast 206 cancer during the first year after cancer diagnosis. 23 This increase may reflect a practice effect, that is an 207 improvement due to becoming familiar with the testing procedures and the cognitive tasks but also due to a 208 lower performance at baseline because of the overwhelming experience of a cancer diagnosis, and fear of 209 treatments and prognosis, that may have dissipated after one year. 24 Indeed, in the present study, borderline 210 anxiety (a score equal to or above eight in the anxiety sub score of the HADS) was associated with MoCA scores 211 at baseline, and patients proposed for radical prostatectomy had the lowest mean MoCA scores and the 212 highest prevalence of borderline anxiety. However, this may not explain the low baseline MoCA scores in 213 patients proposed for ADT and chemotherapy, as the prevalence of borderline anxiety was low in this group. 214

Pain associated with bone metastases could explain lower cognitive performance at baseline, although this 215 assessment was usually performed after three weeks of antiandrogens for pain management and flare 216 prevention. Pathological alterations due to cancer and the control of the disease after one year may explain 217 low cognitive performance at baseline and improvement thereafter, respectively. 218

Cognitive decline, defined as having a variation in MoCA scores over time below 1.5 SD of the variation in the 219 cohort, was consistently more frequent in participants treated with ADT, regardless of the duration of ADT or 220 associated treatments, and the incident or recurrent nature of the disease. This result supports the evidence 221 from previous studies reporting an association of ADT with cognitive decline. 4 In cross sectional evaluations, a 222 higher educational level has been associated with better cognitive performance. 25 However similar or higher 223 rate of decline in some cognitive domains were reported in older adults with higher vs. lower education. 26 reported in individuals with higher education. 27 In the present study, patients with more than 12 years of 226 education were more likely to belong to the group with the worst variation in cognitive scores over one year 227 of follow up, but no association with incident cognitive impairment was observed. 228

Most of the cases with cognitive decline (13 in 22) had high baseline MoCA score which decreased at least 229 four points, while remaining within the normal range for the specific age and education group. In the other 230 hand, most cases of incident cognitive impairment (also 13 in 22) had a decrease in MoCA scores between one 231 and three points. Future assessments of the participants, as well as confirmation of cognitive impairment with 232 a battery of neuropsychological tests and a neurologist diagnosis are needed to refine these results, 233 considering in one hand, that a very high or low scores at baseline or at one year may be due to chance only, 234 being the variation observed a result of the phenomenon of regression to the mean, and, in the other hand, 235 that the MoCA is a screening test. 236

In another longitudinal study of cognitive performance over a five-year period in patients with breast cancer, 237 the variation in MoCA scores in the first year of follow-up was a significant predictor of long-term cognitive 238 decline. Although, population-and cancer-specific differences may not allow to extrapolate the findings to the 239 present study. The incidence of cognitive impairment at one year was similar to the observed among women 240 with breast cancer one-year after cancer diagnosis and using the MoCA (8.1%). 28 These are two different 241 populations of patients with cancer, regarding not only sex but also age and treatments. To our knowledge, 242 there are no studies reporting the incidence of cognitive impairment in prostate cancer patients. 11 Patients 243 treated with ADT were more likely to develop cognitive impairment, a consistent observation considering ADT 244 alone or with radiotherapy, although none of the participants treated with ADT and chemotherapy had 245 incident cognitive impairment. Patients proposed for chemotherapy were younger than those with ADT, which 246 could explain this difference in the cognitive impairment incidence, as well as unmeasured factors related to 247 overall health and lifestyle. Additionally, docetaxel may not have deleterious effects in cognitive function as 248 other drugs or combinations of drugs used in other cancers. Finally, this null result should be interpreted considering that there was a small number of patients treated with this drug, precluding a definitive conclusion 250 on the effect of docetaxel on cognitive function. 251

The first COVID-19 case in Portugal was reported on March 2 nd 2020, and the NEON-PC cohort evaluations 252 were suspended from March 9 th to July 1 st 2020. The first general lockdown occurred from March 22 nd to April 253 30 th 2020 and the second between January 16 th to March 15 th 2021, during which the general population was 254 forbidden from using public spaces, and compulsory confinement was legally imposed, except for basic 255 shopping necessities, health consultations and treatments, and going to work when working from home was 256 not possible. 29 Total confinement and restrictions to normal daily activities since March 2020 have caused 257 many alterations in everyone's life, with a decrease in physical activity and an increase in sedentary 258 behaviours, 30 and changes in eating patterns. 31 Moreover, the reduction in contact with nature was associated 259 with worse mental health, 32 and sleep problems were frequent during the COVID-19 pandemic. 33 ADT has 260 been associated with a higher risk for weight gain and metabolic syndrome, 34 depression 35 and sleep 261 disturbances. 36 These adverse effects of ADT are associated with cognitive dysfunction, 37-41 acting as potential 262 mediators of the effect of ADT on cognitive performance. We observed a negative effect of ADT on the 263 incidence of cognitive impairment, but only after the COVID-19 pandemic, which may be explained by a 264 worsening effect of the pandemic in the prevalence of metabolic syndrome, depression and sleep problems 265 among patients who received ADT. 266

This is the largest prospective study comparing cognitive decline in patients with prostate cancer treated with 268 or without ADT, and the first to report cognitive impairment cumulative incidence in these patients. Although 269 neuropsychological tests are considered the gold standard to assess cognitive performance, 42 which and how 270 many tests to include to assess which cognitive domains, and the criteria to define cognitive impairment have 

Availability of data and materials: The datasets generated and analysed in this study will not be publicly 301 available given that the included patients do not specifically provide their consent for public sharing of their 302 data and that anonymization is unlikely to be feasible, since the identification of patients treated in only one 303 institution within a relatively short period may be possible when taking socio-demographic and clinical 304 characteristics into account. 305

Funding: This study was funded by the European Regional Development Fund through the Operational (6 months 

The Risk of New Onset Dementia and/or Alzheimer Disease 350 among Patients with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review

A review of prostate cancer treatment impact on the CNS and cognitive 353 function

Cognitive impairment among prostate cancer patients: an overview of 355 reviews

Environmental enrichment: A concept analysis

Cognitive decline in patients with prostate cancer: study protocol 362 of a prospective cohort, NEON-PC

MoCA: a brief 364 screening tool for mild cognitive impairment

Validation study of a Portuguese 367 version of the Hospital Anxiety and Depression Scale. Psychology, health & medicine

Não paramos -Estamos on: Resposta de Portugal à COVID-19

We are on: Portugal's response to COVID-19

Changes in physical activity and sedentary behaviours from before 402 to during the COVID-19 pandemic lockdown: a systematic review

The impact of COVID-19 lockdown on disordered 405 eating behaviors: the mediation role of psychological distress

Exposure to nature and mental health outcomes 408 during COVID-19 lockdown. A comparison between Portugal and Spain

Sleep problems during the COVID-411 19 pandemic by population: a systematic review and meta-analysis

Quantifying the evidence for the risk 414 of metabolic syndrome and its components following androgen deprivation therapy for prostate cancer: a 415 meta-analysis

Association of androgen deprivation therapy and depression

Insulin resistance as a key link for the increased risk of cognitive impairment in the 426 metabolic syndrome

The influence of depression on cognitive decline in 428 community-dwelling elderly persons

Connections between sleep and cognition in older adults

International Cognition and Cancer Task Force 433 recommendations to harmonise studies of cognitive function in patients with cancer