Effect of intermittent fasting with or without caloric restriction on prostate cancer growth and survival in SCID mice.

INTRODUCTION: Caloric restriction (CR) delays cancer growth in animals, though translation to humans is difficult. We hypothesized intermittent fasting (i.e., intermittent extreme CR), may be better tolerated and prolong survival of prostate cancer (CaP) bearing mice. METHODS: We conducted a pilot study by injecting 105 male individually-housed SCID mice with LAPC-4 cells. When tumors reached 200 mm(3), 15 mice/group were randomized to one of seven diets and sacrificed when tumors reached 1,500 mm(3): Group 1: ad libitum 7 days/week; Group 2: fasted 1 day/week and ad libitum 6 days/week; Group 3: fasted 1 day/week and fed 6 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 4: 14% CR 7 days/week; Group 5: fasted 2 days/week and ad libitum 5 days/week; Group 6: fasted 2 day/week and fed 5 days/week via paired feeding to maintain isocaloric conditions to Group 1; Group 7: 28% CR 7 days/week. Sera from mice at sacrifice were analyzed for IGF-axis hormones. RESULTS: There were no significant differences in survival among any groups. However, relative to Group 1, there were non-significant trends for improved survival for Groups 3 (HR 0.65, P = 0.26), 5 (0.60, P = 0.18), 6 (HR 0.59, P = 0.16), and 7 (P = 0.59, P = 0.17). Relative to Group 1, body weights and IGF-1 levels were significantly lower in Groups 6 and 7. CONCLUSIONS: This exploratory study found non-significant trends toward improved survival with some intermittent fasting regimens, in the absence of weight loss. Larger appropriately powered studies to detect modest, but clinically important differences are necessary to confirm these findings.

Is a positive bladder neck margin truly a T4 lesion in the prostate specific antigen era? Results from the SEARCH Database.

PURPOSE: Positive bladder neck margins after radical prostatectomy are currently designated as pT4 lesions. However, to our knowledge the prognostic significance of a positive bladder neck margin in the prostate specific antigen era is unknown. We examined the association between positive bladder neck margins and prostate specific antigen recurrence relative to other pathological findings. MATERIALS AND METHODS: We examined 1,722 men from the Shared Equal Access Research Cancer Hospital Database who were treated with radical prostatectomy without lymph node metastases. Time to prostate specific antigen recurrence was compared in men with positive vs negative bladder neck margins using Cox proportional hazards models adjusted for multiple clinical and pathological features. RESULTS: A positive bladder neck margin in 79 patients (5%) was significantly associated with other poor prognostic features, including higher prostate specific antigen, higher pathological Gleason sum, extracapsular extension, seminal vesicle invasion and other positive margins. After adjusting for clinical and pathological characteristics positive bladder neck margins were associated with an increased risk of prostate specific antigen recurrence (HR 1.52, 95% CI 1.06-2.19, p = 0.02). Relative to organ confined margin negative disease a positive bladder neck margin associated with other positive margins showed a recurrence risk that was similar to that of seminal vesicle invasion (HR 4.14, 95% CI 2.55-6.73 and HR 4.22, 95% CI 3.08-5.78, respectively, each p <0.001). An isolated positive bladder neck margin was a rare event, noted in 15 patients (0.7%). In these men the recurrence risk was difficult to estimate due to the small number. However, the HR was similar to that in men with nonbladder neck positive margins or extracapsular extension (HR 2.65, 95% CI 0.97-7.25, p = 0.06 and HR 2.19, 95% CI 1.71-2.82, p <0.001, respectively). CONCLUSIONS: In the current study a positive bladder neck margin was frequently associated with other adverse features. When it was concomitant with other positive margins, a positive bladder neck margin was associated with a progression risk similar to that of seminal vesicle invasion (T3b disease). Although men with an isolated positive bladder neck margin had a more favorable pathological profile, there were too few of them to assess outcome reliably. However, the limited data suggest that they may best be categorized as having pT3a disease.

The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model.

PURPOSE: Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model. EXPERIMENTAL DESIGN: Individually caged male severe combined immunodeficient mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 x 10(6) LNCaP cells (day 0) and sacrificed when tumors were >or=1,000 mm(3). RESULTS: Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001). Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors. CONCLUSIONS: These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.

Obesity and prostate cancer: epidemiology and clinical implications.

OBJECTIVES: Both obesity and prostate cancer (PCa) are epidemic in Western society. Although initial epidemiological data appeared conflicting, recent studies have clarified the association between obesity and PCa. Therefore, we sought to review the epidemiological data linking obesity and PCa with an emphasis on the clinical implications and how to improve outcomes among obese men. METHODS: A PubMed search using the keywords "prostate cancer" and "obesity" was performed. Relevant articles and references were reviewed for data on the association between obesity and PCa. RESULTS: Recent data suggest obesity is associated with reduced risk of nonaggressive disease but increased risk of aggressive disease. This observation may be explained in part by an inherent bias in our ability to detect PCa in obese men (lower PSA values and larger sized prostates, making biopsy less accurate for finding an existent cancer), which ultimately leads to increased risk of cancer recurrence after primary therapy and increased PCa mortality. Despite this detection bias potentially contributing to more aggressive cancers, multiple biological links also exist between obesity and PCa including higher estradiol, insulin, free IGF-1, and leptin levels, and lower free testosterone and adiponectin levels, all of which may promote more aggressive cancers. CONCLUSIONS: The association between obesity and PCa is complex. Emerging data suggest obesity increases the risk of aggressive cancer, while simultaneously decreasing the risk of more indolent disease. This is likely driven by both "biological" and "nonbiological" causes. Simple changes in clinical practice patterns can reduce the impact of nonbiological causes and may help improve PCa outcomes among obese men.