Neil Fleshner

Serum and Tissue Lycopene and Biomarkers of Oxidation in Prostate Cancer Patients: A Case-Control Study

Dietary intake of tomatoes and tomato products containing lycopene, an antioxidant carotenoid, has been shown in recent studies to reduce the risk of cancer. This study was conducted to investigate the serum and prostate tissue lycopene and other major carotenoid concentrations in cancer patients and their controls. Serum lipid and protein oxidation was also measured. Twelve prostate cancer patients and 12 age-matched subjects were used in the study. Significantly lower serum and tissue lycopene levels (44%, p = 0.04; 78%, p = 0.050, respectively) were observed in the cancer patients than in their controls. Serum and tissue beta-carotene and other major carotenoids did not differ between the two groups (p = 0.395 and p = 0.280, respectively). Although there was no difference (p = 0.760) in serum lipid peroxidation between cancer patients and their controls (7.09 +/- 0.74 and 6.81 +/- 0.56 mumol/l, respectively), serum protein thiol levels were significantly lower among the cancer patients (p = 0.026). This study demonstrates that the status of lycopene but not other carotenoids in prostate cancer patients is different from controls. The role of dietary lycopene in preventing oxidative damage of biomolecules and thereby reducing the risk of prostate cancer needs to be evaluated in future studies.

Comparison of Health-Related Quality of Life 5 Years After SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial

PURPOSEnThe American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial comparing radical prostatectomy (RP) and brachytherapy (BT) closed after 2 years due to poor accrual. We report health-related quality of life (HRQOL) at a mean of 5.3 years for 168 trial-eligible men who either chose or were randomly assigned to RP or BT following a multidisciplinary educational session.nnnPATIENTS AND METHODSnAfter initial lack of accrual, a multidisciplinary educational session was introduced for eligible patients. In all, 263 men attended 47 sessions. Of those, 34 consented to random assignment, 62 chose RP, and 94 chose BT. Five years later, these 190 men underwent HRQOL evaluation by using the cancer-specific 50-item Expanded Prostate Cancer Index Composite, the Short Form 12 Physical Component Score, and Short Form 12 Mental Component Score. Response rate was 88.4%. The Wilcoxon rank sum test was used to compare summary scores between the two interventions.nnnRESULTSnOf 168 survey responders, 60.7% had BT (9.5% randomly assigned) and 39.3% had RP (9.5% randomly assigned). Median age was 61.4 years for BT and 59.4 for RP (P = .05). Median follow-up was 5.2 years (range, 3.2 to 6.5 years). For BT versus RP, there was no difference in bowel or hormonal domains, but men treated with BT scored better in urinary (91.8 v 88.1; P = .02) and sexual (52.5 v 39.2; P = .001) domains, and in patient satisfaction (93.6 v 76.9; P < .001).nnnCONCLUSIONnAlthough treatment allocation was random in only 19%, all patients received identical information in a multidisciplinary setting before selecting RP, BT, or random assignment. HRQOL evaluated 3.2 to 6.5 years after treatment showed an advantage for BT in urinary and sexual domains and in patient satisfaction.

Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer

PURPOSEnTo evaluate the effects of androgen-deprivation therapy (ADT) on cognitive function in men with nonmetastatic prostate cancer (PC).nnnPATIENTS AND METHODSnThe following three groups of men age 50 years or older and matched on age and education were enrolled: patients with PC starting continuous ADT (n = 77), patients with PC not receiving ADT (PC controls, n = 82), and healthy controls (n = 82). A battery of 14 neuropsychological tests, examining eight cognitive domains, was administered at baseline, 6 months, and 12 months. Changes in cognitive scores over time were analyzed using the following three approaches: multivariable linear regression; the proportion of participants per group with 1 standard deviation (SD) or greater declines, and the proportion of participants who declined by at least 1.5 SD on two or more tests.nnnRESULTSnThe mean age and education level of participants were 68.9 years (range, 50 to 87 years) and 15.4 years of education (range, 8 to 24 years), respectively. Adjusted for age and education, all three cohorts had similar cognitive scores at baseline other than in one test of working memory. In adjusted regressions, ADT use was not associated with significant changes in the domains of attention/processing speed, verbal fluency, verbal memory, visual memory, or cognitive flexibility at either 6 months (all P > .05) or 12 months (all P > .05). One test each of immediate memory (P = .029), working memory (P = .031), and visuospatial ability (P = .034) were worse among ADT users than controls at 12 months, but these findings were not confirmed using other analytic approaches.nnnCONCLUSIONnThere is no consistent evidence that 12 months of ADT use has an adverse effect on cognitive function in elderly men with PC.

Impact of a Multi-Disciplinary Patient Education Session on Accrual to a Difficult Clinical Trial: The Toronto Experience With the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial

PURPOSEnRandom assignment to clinical trials involving different treatment modalities can be difficult. We describe our experience with the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; ACOSOG Z0070 NCIC PR10), a randomized trial for early-stage prostate cancer comparing radical prostatectomy (RP), and brachytherapy (BT). A multidisciplinary educational session was developed to improve patient understanding of treatment options and to facilitate accrual.nnnPATIENTS AND METHODSnProstate cancer referrals were screened and men who met favorable risk criteria (T1c/T2a, prostate-specific antigen [PSA] < 10 ng/mL, Gleason < or = 6) were invited to a structured education session before a specialty consultation. Men and their partners viewed the SPIRIT informed-consent video and heard from a cancer patient who described his participation in a randomized trial. Then, a urologist and radiation oncologist together compared and contrasted RP and BT to establish the rationale for the trial.nnnRESULTSnIn May 2002, SPIRIT opened for accrual and was endorsed by the University Health Network urologists and radiation oncologists. The first 27 eligible patients were approached about SPIRIT, consulted both specialties, and viewed an educational video. No patients consented. The multidisciplinary education session was then introduced. Forty-seven education sessions with 263 patients resulted in 34 consents. Of 203 patients who were suitable for the study but declined random assignment, 62 chose surgery, 94 chose brachytherapy, three patients chose external radiotherapy, and 11 chose no treatment. Consent rates for eligible and suitable patients were one in six.nnnCONCLUSIONnMen who understand their treatment options and trial rationale as presented jointly by representative specialists from competing treatment modalities may be better equipped to make an informed decision and are more likely to consent to random assignment.

Cigarette smoking patterns in patients after treatment of bladder cancer

BACKGROUNDnAssessment of smoking status and identification of those most likely to continue smoking are important in the management of patients who have bladder cancer, because continued smoking following diagnosis and treatment increases the likelihood of treatment-related complications, recurrence, second primary malignancies, and morbidity and mortality.nnnMETHODSnPatients (n = 224) receiving follow-up care of previously treated bladder cancers completed a brief written survey assessing their post-diagnosis smoking patterns.nnnRESULTSnDespite the risks of continued smoking, 69% of the patients who had been active smokers at the time of diagnosis (n = 84) reported smoking at some point following the diagnosis and 45% reported smoking at the time of assessment. Patients diagnosed at earlier stages were more likely to continue smoking. Patients diagnosed at later stages were 2.80 times more likely to be continuous abstainers than those diagnosed sooner (95% CI, 1.08-7.25).nnnCONCLUSIONSnThe findings underscore the need to assess smoking status and provide smoking-cessation advice and counseling within routine comprehensive care of bladder cancer patients.

Antiproliferative Mechanisms of the Flavonoids 2,2′-Dihydroxychalcone and Fisetin in Human Prostate Cancer Cells

We have previously demonstrated the antiproliferative effect of two flavonoids—2,2′-dihydroxychalcone (DHC), a novel synthetic flavonoid, and fisetin, a naturally occurring flavonol—in prostate cancer cells. In this study, we further examine the mechanisms of these compounds on survival and proliferation pathways. DHC and fisetin (1–50 μM) caused a dose-dependent reduction in viability, a concomitant increase in apoptosis in PC3 cells at 72 h, and a decrease in clonogenic survival at 24 h treatment. DHC was considerably more potent than fisetin in these cytotoxicity assays. The mechanism of accelerated cellular senescence was not activated by either compound in PC3 or lymph node carcinoma of the prostate (LNCaP) cells. Gene expression alterations in PC3 and LNCaP cells treated with 15 μM DHC and 25 μM fisetin for 6 to 24 h were determined by oligonucleotide array. Amongst the most highly represented functional categories of genes altered by both compounds was the cell cycle category. In total, 100 cell cycle genes were altered by DHC and fisetin including 27 genes with key functions in G2/M phase that were downregulated by both compounds. Other functional categories altered included chromosome organization, apoptosis, and stress response. These results demonstrate the multiple mechanisms of antitumor activity of DHC and fisetin in prostate cancer cells in vitro.

Levels of sex hormones have limited effect on cognition in older men with or without prostate cancer

Androgen deprivation therapy is commonly used to treat prostate cancer, but by lowering testosterone levels it may affect cognitive function. However, the relationship between testosterone and cognition remains unclear. We examined the relationship between sex hormones (total testosterone, bioavailable testosterone, and estradiol) and cognition in a cross-sectional study of 198 older men (mean age 69.2 years, median education 16 years) with and without prostate cancer, none of who had started androgen deprivation therapy. We found relationships between total testosterone and two of four measures of working memory. Similar relationships were found in regression analyses adjusted for age and education with both total testosterone and estradiol. Neither hormone was related to other cognitive domains, nor was bioavailable testosterone level. Although cognitive function was not generally related to sex hormone levels in older men, there may be a weak association with working memory. These results may help guide future studies.

Diminished Efficacy of Bacille Calmette-Guérin Among Elderly Patients with Nonmuscle Invasive Bladder Cancer

OBJECTIVEnBacille Calmette-Guérin (BCG) is recommended as adjunctive therapy among patients with high-risk nonmuscle-invasive bladder cancer (BC). Given that immune response is attenuated with age, we set out to determine the impact of age on response to BCG.nnnMATERIALS AND METHODSnWe searched our prospective bladder information system and limited our search to patients with incident BC completely resected at transurethral resection (TUR) who completed a full induction course of BCG. We then analyzed the impact of age on outcome. Age was analyzed both dichotomously (greater or less than 75 years) as well as by 10-year increments. The main outcomes were recurrence or progression-free survival. Log-rank and multivariable Cox proportional-hazard analyses, adjusting for clinical and pathologic features (age, multifocality, pathologic stage, grade and associated carcinoma in situ, maintenance, and restaging) were used.nnnRESULTSnThis cohort included 238 patients. Baseline parameters were similar aside from tumor number. Progression-free survival differed between age groups when examined either dichotomously or via 10-year increments. The 2-year progression-free survival was 87% among patients <75 years vs 65% in patients >75 years (log rank P <.001). An age-dependent trend was noted when analyzed by 10-year increment (log-rank for trend P = .011). On multivariable analysis, age was an independent risk factor for progression (HR = 2.9, 95% CI 1.7-4.9). Recurrence-free survival was similar among age strata.nnnCONCLUSIONnWe demonstrated that advanced age is associated with higher progression rates despite BCG. The care of BC in the elderly population is of increasing concern and should be addressed in a prospective clinical study.

A BRCA1 mutation is not associated with increased indicators of oxidative stress.

BACKGROUNDnSeveral functions have been attributed to the BRCA1 protein. A recent study suggests that BRCA1 is involved in the cellular antioxidant response by inducing the expression of genes involved in the antioxidant defense system and thus conferring resistance to oxidative stress. It is possible that individuals with a BRCA1 mutation might be susceptible to the effects of oxidative stress. The aim of this study was to evaluate whether women with a BRCA1 mutation exhibit increased indicators of oxidative stress.nnnPATIENTS AND METHODSnWe measured 3 markers of oxidative stress in vivo, the amounts of serum malondialdehyde and protein thiols, and 8-oxo-2-deoxyguanosine (8-oxodG) levels in 25 unaffected BRCA1 mutation carriers and 25 noncarrier control subjects.nnnRESULTSnThere was no significant difference in serum malondialdehyde levels (P=.41), serum thiol levels (P=.85), or the number of 8-oxodG lesions (P=.49) in BRCA1 mutation carriers versus noncarriers.nnnCONCLUSIONnThe results of this study suggest that the presence of a heterozygous BRCA1 mutation is not associated with increased levels of indicators of oxidative stress in serum or lymphocytes. Future studies are warranted to evaluate whether strategies aimed at minimizing oxidative stress might aid in the prevention of hereditary breast cancer.