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.”

Men Who Receive Androgen Deprivation Therapy for Prostate Cancer Have Higher Risk of Cardiovascular Disease

“For men with prostate cancer (PCa), the risk for incident cardiovascular disease (CVD) is increased with androgen deprivation therapy (ADT), according to a study published online March 2 in the Journal of Clinical Oncology.

“Sean O’Farrell, from King’s College London, and colleagues used data on filled drug prescriptions in Swedish national health care registers to examine the risk of CVD associated with ADT in men with PCa. Data were collected in a cohort of 41,362 men with PCa on ADT and an age-matched PCa-free comparison cohort of 187,875 men. Overall, 10,656 men were on antiandrogens (AAs); 26,959 were on gonadotropin-releasing hormone (GnRH) agonists; and 3,747 underwent surgical orchiectomy from 2006 to 2012.

“Compared to the comparison cohort, the researchers found that the risk of CVD was increased in men on GnRH agonists (hazard ratio for incident CVD, 1.21) and in those who underwent orchiectomy (hazard ratio, 1.16). The risk of incident CVD was decreased for men on AAs (hazard ratio, 0.87). Men who experienced two or more cardiovascular events before therapy had the highest CVD risk during the first six months of ADT versus the comparison cohort, with hazard ratios of 1.91 for GnRH agonist therapy; 1.60 for AAs; and 1.79 for orchiectomy.”

ADT Increases Risk for Cardiovascular Disease in Men with Prostate Cancer

“Patients with prostate cancer who received androgen-deprivation therapy demonstrated an increased risk for cardiovascular disease, according to study results.

“Men with a previous history of cardiovascular events were at a particularly increased risk for cardiovascular disease (CVD) with androgen-deprivation therapy (ADT), results showed.

“Sean O’Farrell, BSc, MRes,of the division of cancer studies at King’s College London School of Medicine, and colleagues used the Swedish national health care registries to identify 41,362 patients who received ADT for prostate cancer. The analysis also included a control group of 187,785 age-matched, cancer-free men…

“ ‘Our study suggests an increased risk of CVD within the first year from starting GnRH agonist therapy or orchiectomy, especially in men with history of a CVD event within 1 year before ADT,’ O’Farrell and colleagues concluded. ‘There should be solid indication of use of ADT so that the perceived benefit outweighs possible harm. This is particularly important in men with a recent history of CVD.’ “

Phase III Trial Shows Improved Survival With Long‑Term Androgen-Deprivation Therapy Plus High-Dose Radiotherapy in Localized Prostate Cancer

“In the Spanish phase III DART01/05 GICOR trial reported in Lancet Oncology, Zapatero and colleagues found that long-term androgen-deprivation therapy (ADT) increased biochemical disease-free survival and overall survival vs short-term ADT when combined with high-dose radiotherapy in men with localized prostate cancer.

“In this open-label trial, 355 patients were randomly assigned between November 2005 and December  2010 to receive 4 months of ADT (n = 178) or 24 months of ADT (n = 177) following three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range, 76–82 Gy). Patients had to have clinical stage T1c–T3b, N0, M0 prostate adenocarcinoma with intermediate or high risk based on 2005 National Comprehensive Cancer Network criteria.

“The short-term ADT group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaenous goserelin (Zoladex) 2 months before and 2 months in combination with high-dose radiotherapy, with flutamide at 750 mg/d or bicalutamide at 50 mg/d added during the first 2 months of treatment. Patients in the long-term ADT group continued with the same luteinizing hormone–releasing hormone analog every 3 months for 24 months. The primary endpoint was biochemical disease-free survival on intention-to-treat analysis.”

Seeds Top EBRT as Boost Tx in Prostate Cancer

“Low-dose brachytherapy boosts held prostate cancer in check significantly better than dose-escalated external-beam radiation therapy (EBRT) in men with unfavorable-risk disease, a randomized trial showed.

“Patients treated with brachytherapy after androgen deprivation therapy (ADT) and whole-pelvis EBRT had an estimated 9-year relapse-free survival (RFS) of 83% compared with 63% for patients who received a conformal EBRT boost. The difference in favor of brachytherapy emerged after 5 years of follow-up, Scott Tyldesley, MD, of the British Columbia Cancer Agency in Vancouver, reported here at the Genitourinary Cancers Symposium.

” ‘In the context of 12 months of androgen deprivation therapy and whole pelvis external beam radiotherapy, treatment with a low-dose pelvic brachytherapy boost results in a 50% reduction in biochemical relapse compared to dose-escalated EBRT to 78 Gray,’ Tyldesley said. ‘At 6.5 years of follow-up, there was no difference in overall survival, prostate cancer specific survival, or metastasis-free survival.’

“However, ‘there was increased late grade 3 or higher GU toxicity with the low-dose rate boost, a 5% to 6% increase in the prevalence of late GU toxicity,’ he said.”