Diet and lifestyle considerations for patients with prostate cancer.

PURPOSE: To review the literature and provide recommendations on diet and lifestyle considerations in patients with prostate cancer using evidence from randomized controlled trials (RCTs) with additional considerations based on observational evidence. MATERIALS AND METHODS: We initiated our search on ClinicalTrials.gov combining the term "prostate cancer" with a variety of diet and lifestyle factors. We then supplemented our summary of publications from registered trials by including other publications available on Pubmed. RESULTS: There is a well-established benefit of exercise for improving functional outcomes and pelvic floor muscle training for improving treatment-related adverse effects. Multimodality interventions that integrate several factors (e.g., low-saturated fat, plant-based, whole-food diets with exercise, and stress reduction) appear to have the most clinically significant benefit for patients with prostate cancer. Ongoing multimodality interventions are including the efficacy of implementation strategies as observed outcomes. Limited RCT evidence suggests a clinically significant benefit for guided imagery/progressive muscle relaxation, Pilates, and lycopene-rich diets and a modest benefit for green tea, qigong, massage, and avoidance of nonprescribed vitamin and mineral supplements. Observational and single arm trial evidence indicates a need for further exploration of acupuncture, coffee, cruciferous vegetables, fish, Larrea tridentata, mushrooms, and vegetable-derived fats and avoidance of eggs, dairy, poultry with skin, processed red meat, and saturated fat. Published trials suggest no benefit from hypnosis, milk thistle, pomegranate, soy, or omega-3 fatty acid supplementation. CONCLUSIONS: Our search demonstrated that most diet and lifestyle factors identified from observational studies have limited data from RCTs. Few items have shown early evidence of benefit. The best recommendation for patients with prostate cancer is to form a habit of wellness through healthy eating, aerobic and resistance exercise, and psychological well-being. Future trial development should consider how interventions can be implemented into real world practice.

How current reporting practices may mask differences: A call for examining cancer-specific demographic enrollment patterns in cancer treatment clinical trials.

BACKGROUND: A lack of diversity among clinical trial (CT) participants remains a critical problem. Few studies have examined recruitment variability in cancer treatment CTs by cancer type. Given the increasing organ-specific specialization of oncologic care, an understanding of this variability may affect institutional recruitment practices. METHODS: This study examines three data sources from 2010 through 2014. The analyzed sample includes 3,580 CT participants identified in the institutional Clinical Trials Management System (CTMS) database and 20,305 incident cases of invasive cancer within a Comprehensive Cancer Center (CCC) institutional catchment area. A total of 341,114 incident cases of primary invasive cancer were identified through the California Cancer Registry (CCR). The primary study measurements were sociodemographic characteristics of the three populations (age, sex, race/ethnicity, and health insurance). RESULTS: Racial/ethnic disparities were observed, with more incident cases of Whites seen in cancer center (68%) and enrolled in CTs (72%) compared to incident cases in catchment area (67%) (p < 0.001) overall. More older adults (65) were enrolled in prostate cancer CTs (58%) than seen in cancer center (45%) (p < 0.001). Alternatively, fewer older adults were enrolled in breast and colorectal CTs than seen in cancer center (p < 0.001). Among colon (p < 0.001), breast (p < 0.001), and prostate (p<0.001) cancer types, insurance type significantly varied between incident cases in catchment area, cancer center, and among CT participants. For colorectal cancer, no difference in sex distribution was observed overall. A significant difference in insurance type within each cancer type was observed (p < 0.001). CONCLUSIONS: These findings suggest that reporting overall recruitment frequencies may mask differences by cancer type.

68Ga-PSMA-11 PET Imaging of Response to Androgen Receptor Inhibition: First Human Experience.

The purpose of this work was to evaluate the effect of androgen receptor (AR) inhibition on prostate-specific membrane antigen (PSMA) uptake imaged using 68Ga-PSMA-11 PET in a mouse xenograft model and in a patient with castration-sensitive prostate cancer. METHODS: We imaged 3 groups of 4 mice bearing LNCaP-AR xenografts before and 7 d after treatment with ARN-509, orchiectomy, or control vehicle. Additionally, we imaged one patient with castration-sensitive prostate cancer before and 4 wk after treatment with androgen deprivation therapy (ADT). Uptake on pre- and posttreatment imaging was measured and compared. RESULTS: PSMA uptake increased 1.5- to 2.0-fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509 but not with vehicle. Patient imaging demonstrated a 7-fold increase in PSMA uptake after the initiation of ADT. Thirteen of 22 lesions in the imaged patient were visualized on PSMA PET only after treatment with ADT. CONCLUSION: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effect seen in cell and animal models can be recapitulated in humans. A better understanding of the temporal changes in PSMA expression is needed to leverage this effect for both improved diagnosis and improved therapy.

A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer.

OBJECTIVE: ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+)-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer. METHODS: Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) < 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels > 150 ng/dl) were eligible. ATN-224 was administered at 2 dose-levels, 300 mg (n = 23) or 30 mg (n = 24) daily, by way of randomization. PSA progression was defined as a ≥ 50% increase (and >5 ng/ml) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the 2 treatment groups. RESULTS: At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% CI 17%-77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21-40(+)) and 26 weeks (95% CI 24-39(+)) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (P = 0.006) and a significant mean PSADT increase (P = 0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. CONCLUSIONS: Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.

A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma.

BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.

The mechanism of action of estrogen in castration-resistant prostate cancer: clues from hormone levels.

BACKGROUND: Estrogen therapy plays a role in the management of castration-resistant prostate cancer (CRPC), although the mechanism of action is not fully known. This current analysis reports the relationship of change in adrenal androgen levels and prostate-specific antigen (PSA) response in patients with CRPC treated with estrogen therapy. PATIENTS AND METHODS: Hormone levels were measured for patients with CRPC treated in a multicenter phase II trial of 2 estrogen-containing compounds, the herbal supplement PC-SPES and diethylstilbestrol (DES), with known efficacy in CRPC. Patients with castrate levels of testosterone were randomized to initially receive either PC-SPES 960 mg t.i.d. or DES 3 mg/day. Levels of testosterone, dihydrotestosterone (DHT), estradiol, estrone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione were obtained at baseline and at 12-week intervals until disease progression. Hormone levels were obtained for 38 patients, 20 treated with PC-SPES and 18 treated with DES. RESULTS: Significant declines between baseline and 12 weeks of treatment were observed in levels of serum testosterone (P < .001), estrone (P = .02), and DHEA (P < .001). The percent changes at 12 weeks in these hormone levels were inversely proportional to baseline values as measured by Spearman's rank correlation (testosterone: -0.41, P = .01; estrone: -0.64, P = .0001; DHEA: -0.39, P = .02). Levels of SHBG increased in almost all of the patients (97%), with a median percent increase of > 5-fold (P < .0001). Of the 38 evaluable patients, 15 (39% [95% CI, 24%-57%]) experienced a > 50% decline in PSA level. There was no significant difference between treatment groups or between responders and nonresponders in baseline distributions for any of the hormones. At follow-up, 73% of the responders had a decline in the level of DHEA-S compared with 41% of the nonresponders, resulting in a difference in the distribution of the percent change between the subsets (Mann-Whitney test: P = .03). Conversely, 64% of the responders compared with 30% of the nonresponders experienced an increase in DHT, with differing distributions of percent change (P = .02). CONCLUSION: Androgens decline in response to estrogen therapy. A decline in DHEA-S and a rise in DHT are both associated with a decline in PSA while patients receive estrogen therapy.