Men Receiving Androgen Deprivation Therapy may Experience Cognitive Impairment

“Cognitive impairment can occur in cancer patients who are treated with a variety of therapies, including radiation therapy, hormone therapy, and chemotherapy. After chemotherapy treatment it is commonly called ‘chemo brain.’ Signs of cognitive impairment include forgetfulness, inability to concentrate, problems recalling information, trouble multi-tasking and becoming slower at processing information. The number of people who experience cognitive problems following cancer therapy is broad, with an estimate range of 15 to 70 percent.

“There have been several studies analyzing this side effect in breast cancer patients, but few have investigated cognitive impairment following androgen deprivation therapy (ADT) for men being treated prostate cancer. A new Moffitt Cancer Center study indicated that men who are on androgen deprivation therapy have greater odds of experiencing impaired cognitive function.

“Androgen deprivation therapy is commonly used to treat prostate cancer, often on an open-ended basis for therapy of advanced prostate cancer. It is estimated that 44 percent of men with prostate cancer undergo ADT at some point. The goal of this type of therapy is to block the male hormones, including testosterone, from stimulating the growth of the prostate cancer cells. However, the side effect of ADT on cognitive function in men with prostate cancer has not been measured as much.”


Statin Drugs Can Delay Prostate Cancer Progression in Patients Receiving Androgen Deprivation Therapy, Study Shows

“Men who went on cholesterol-lowering statin drugs when they began androgen deprivation therapy for prostate cancer had a longer time in which their disease was under control than did men who didn’t take statins, a clinical trial led by Dana-Farber Cancer Institute investigators shows.

“In a study published online today by JAMA Oncology, the researchers report that men who had been taking statins since the start of androgen deprivation therapy (ADT) went a median of 27.5 months before their disease began to worsen, compared to 17.4 months for men who didn’t take statins. The trial involved 926 patients, 70 percent of whom had their disease progress during a six-year period.

“ ‘This median 10-month benefit in delaying disease progression suggests that statins could be a valuable addition to our current therapies for prostate cancer,’ says the study’s first author, Lauren Harshman, MD, medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber. ‘These results are supported by multiple prior epidemiologic studies demonstrating that statin use may be associated with improved outcomes in prostate cancer, but require validation.’ “


Cixutumumab Shows No Effect in Metastatic Castration-Resistant Prostate Cancer

“In a randomized phase II trial (SWOG S0925) reported in the Journal of Clinical Oncology, Yu et al found that the addition of cixutumumab to androgen-deprivation therapy did not significantly increase the rate of undetectable prostate-specific antigen (PSA) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. Cixutumumab inhibits the insulin-like growth factor I receptor (IGF-IR).

“In the study, 210 patients from SWOG institutions were randomly assigned between February 2011 and December 2012 within 30 days of starting androgen deprivation to receive bicalutamide daily with a luteinizing hormone-releasing hormone agonist alone (n = 105) or with cixutumumab at 10 mg/kg given intravenously over 1 hour every 2 weeks for seven 28-day cycles. The primary endpoint was rate of undetectable PSA (≤ 0.2 ng/mL) at 28 weeks.

“The cixutumumab and control groups were generally balanced for baseline characteristics, including age (median, 65 and 66 years), PSA level (median, 31 and 37 ng/mL), Gleason score (≥7 in 60% and 78%), race (89% and 84% white), metastasis site (lymph node only in 14% and 9%, bone only in 53% and 60%, both in 18% and 16%, visceral in 14% and 15%), and early-induction androgen deprivation (56% and 62%).”


Radioactive Implants Improve Survival in High-Risk Prostate Cancer

“Results from a randomised controlled trial to compare the use of permanent radioactive implants (brachytherapy) with dose-escalated external beam radiotherapy in patients with prostate cancer show that the men who received brachytherapy were twice as likely to be cancer-free five years later.

“Presenting these results at the 3rd ESTRO Forum in Barcelona, Spain, today (Monday) Professor James Morris, from the Department of Radiation Oncology, Vancouver Cancer Centre, British Columbia Cancer Agency (BCCA), Vancouver, Canada, will say that the ASCENDE-RT trial is the first and only existing trial comparing low-dose-rate prostate brachytherapy (LDR-PB) for the curative treatment of prostate cancer with any other method of radiation therapy delivery.

“The trial enrolled 398 men with cancer that had not spread outside the prostate gland who were judged to be at high risk of treatment failure, based on standard tests for a number of features of the cancer. The patients initially received androgen deprivation therapy (ADT), aimed at reducing levels of the male hormones that stimulate prostate cancer cells to grow. After eight months of ADT, all patients received 46 Gy of external beam radiotherapy to the prostate and regional lymph nodes.”


ADT Affects Long-Term Quality of Life in Patients with Prostate Cancer

“The physical adverse effects associated with continuous androgen deprivation therapy persisted long-term in patients with nonmetastatic prostate cancer, according to study results.

“Approximately 50% of men with prostate cancer will receive ADT, and most of those men will undergo the treatment for 2 to 3 years, according to study background. ADT is associated with several adverse effects that affect the quality of life in patients, such as sexual dysfunction, fatigue, anemia, osteoporosis and muscle loss.

“Shabbir M.H. Alibhai, MD, MSc, FRCPC, of the department of medicine at the University Health Network in Toronto, and colleagues previously evaluated the physical effects of ADT after 12 months. Researchers evaluated data from the same cohort for an additional 2 years to examine long-term adverse effects of the therapy.

“The analysis included 87 men with nonmetastatic prostate cancer who received continuous ADT and two age- and education-matched control groups, one composed of 86 men with prostate cancer who did not receive ADT and one composed of 86 healthy men. The mean age of all participants in the population was 69 years…

“ ‘A reasonable interpretation of our findings is that most of the deleterious effects of ADT on physical function in middle-aged and older men is seen with 6 months of ADT use,’ the researchers wrote. ‘An additional 12 to 30 months of ADT does not appear to lead to much additional decline. …This may be particularly relevant to clinicians who are debating the merits of shorter or longer courses of ADT because it provides more information about physical toxicities of ADT.’ ”


Cixutumumab Adds No Benefit in ADT-Sensitive Prostate Cancer

“Adding cixutumumab to androgen deprivation therapy (ADT) did not significantly increase the undetectable prostate-specific antigen (PSA) rate in men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, according to results of the Southwest Oncology Group (SWOG) S0925 study published in the Journal of Clinical Oncology.

“Evan Y. Yu, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, and colleagues randomized 210 patients to receive either ADT (bicalutamide and luteinizing hormone–releasing hormone agonist) alone or ADT plus cixutumumab. At 28 weeks, the undetectable PSA rate (≤ 0.2 ng/mL) was 40% (42 of 105 patients) in the cixutumumab arm compared with 32.3% (34 of 105 patients) in the ADT-alone arm (relative risk = 1.24, P = .16).

“The median age of patients in the trial was 65, and the median PSA levels in the control and cixutumumab arms were 31 ng/mL and 37 ng/mL, respectively…

“ ‘Although these results fail to confirm preclinical evidence supporting the combination of castration with IGF-1R inhibition by cixutumumab, it is possible that the primary endpoint of undetectable PSA at 28 weeks does not fully capture cixutumumab efficacy,’ concluded the authors.”


Androgen Deprivation Therapy Has Lasting Impact on Function

“For patients with prostate cancer, androgen deprivation therapy (ADT) has a lasting impact on physical function, according to a study published online March 24 in Cancer.

“Shabbir M.H. Alibhai, M.D., from the University Health Network in Toronto, and colleagues examined the impact of ADT on physical function and quality of life over 36 months. They enrolled 87 men with nonmetastatic  who were starting continuous ADT, and two control groups matched by age and education (86 prostate cancer patients without ADT and 86 healthy controls).

“The researchers found that in both control groups there was an initial improvement in the six-minute walk test which then stabilized, while there was no change for ADT users (P = 0.0030). In control groups, grip strength remained stable, but there was a sharp decline in the ADT group by three months, which then remained stable to 36 months (P = 0.0041). Over 36 months, Timed Up and Go scores declined gradually in the ADT group and did not change in control groups (P = 0.0001). In all groups, the aggregate mental quality of life was stable. Declines seen in the first year of ADT use were independent of age and generally persisted during 36 months.”


Low Testosterone During First Year of ADT Linked to Improved Survival

“In an analysis from the PR-7 trial reported in the Journal of Clinical Oncology, Klotz et al found that in men with prostate cancer with biochemical failure after radiotherapy with or without surgery, a nadir serum testosterone level ≤ 0.7 nmol/L during the first year of continuous androgen-deprivation therapy was predictive of improved cause-specific survival and prolonged time to hormone resistance.

“In the PR-7 trial, 1,386 patients were randomly assigned to continuous androgen-deprivation therapy (n = 696) or intermittent androgen-deprivation therapy (n = 690). Of 626 men in the continuous androgen-deprivation therapy group eligible for the current analysis, 226 developed castration-resistant prostate cancer, with a median time to diagnosis of 10.0 years; the 5-year event-free rate was 69%…

“The investigators concluded: ‘Low nadir serum testosterone (ie, < 0.7 nmol/L) within the first year of androgen-deprivation therapy correlates with improved [cause-specific survival] and duration of response to androgen deprivation in men being treated for biochemical failure undergoing [continuous androgen deprivation].’ ”


Testosterone Levels During ADT May Predict Prostate Cancer Outcomes

“A strong reduction in testosterone levels during the first year of androgen deprivation therapy (ADT) correlates with an improved survival in prostate cancer patients undergoing treatment for biochemical failure.

“Men with prostate cancer who had testosterone levels ≤ 0.7 nmol/L had significantly longer survival and longer time to hormone resistance compared with men with higher testosterone levels (P = .015 and P = .02, respectively). Men who had testosterone levels consistently > 0.7 nmol/L had a greater risk of dying from their prostate cancer compared with men with lower hormone levels.

“Those whose testosterone levels increased to ≥ 1.7 nmol/L developed castration resistance more quickly, compared with men whose hormone levels remained steadily ≤ 0.7 nmol/L.

“The current analysis led by Laurence Klotz, MD, of Sunnybrook Health Sciences Centre at the University of Toronto, and colleagues analyzed the prospectively collected testosterone levels and clinical outcomes of the 1,386 men enrolled in the phase III PR-7 trial, which randomized men with biochemically recurrent prostate cancer after primary local therapy to receive either continuous (n = 696) or intermittent (n = 690) ADT…

“But, the editorial authors believe that caution is warranted in interpreting these post hoc results because ‘the primary analysis of the PR-7 study showed that intermittent hormone therapy was non-inferior to continuous therapy with respect to overall survival.’ Therefore, the importance of the further manipulation of testosterone levels in prostate cancer patients after ADT is still unclear. They also point to an ongoing trial, the SWOG-S1216 trial, which is currently evaluating the role of deeper testosterone suppression. ‘Until these or similar results are available, we should not recommend deeper androgen suppression in the first-line setting for men with (metastatic or nonmetastatic) hormone-sensitive prostate cancer,’ concluded Suzman and Antonarakis.”