Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Intraprostatic inflammation is positively associated with serum PSA in men with PSA <4 ng ml(-1), normal DRE and negative for prostate cancer.

BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.

A randomized controlled Alzheimer's disease prevention trial's evolution into an exposure trial: the PREADViSE Trial.

OBJECTIVES: To summarize the ongoing prevention of Alzheimer's disease (AD) by vitamin E and selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. DESIGN: PREADViSE was designed as a double blind randomized controlled trial (RCT). SETTING: SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. PARTICIPANTS: In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. INTERVENTION: In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2x2 factorial structure. MEASUREMENTS: In the RCT, participants completed the memory impairment screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a modified telephone interview of cognitive status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. RESULTS: While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. CONCLUSION: Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials.

Nutrients included in commonly used dietary supplements, such as vitamins C and E, may affect cancer risk. To better understand how supplement use may affect the interpretation of cancer prevention trials, we examined dietary supplement use among participants in the Prostate Cancer Prevention Trial, a double-blind, placebo-controlled trial of the drug finasteride (Proscar) for the primary prevention of prostate cancer. Of 15,387 men who completed food frequency questionnaires and dietary supplement questionnaires, 44.3% used a multivitamin, 35% used single supplements of vitamin C or E, and 10-15% used antioxidant mixtures or single supplements of vitamins A and D, zinc, or beta-carotene at least three times per week. The strongest correlates of supplement use were higher education and lower body mass index (p < 0.001), and whites and Asians were more likely to use multivitamins and single supplements of vitamins C and E than were blacks and Hispanics. Supplement users obtained 87% of their total daily vitamin E intake, 61-64% of vitamins A, C, and D, and about half of beta-carotene, folate, and zinc from supplements. Because supplements, especially antioxidants, may confer independent cancer-preventive effects, analytic models of study findings should include exposure measurement of dietary supplements with appropriate tests for interaction. Our results can be generalized to similar chemoprevention trials.

SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial.

PURPOSE: Growing evidence implies that selenium and vitamin E may decrease the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized prospective double-blind study designed to determine whether selenium and vitamin E decrease the risk of prostate cancer in healthy men. MATERIALS AND METHODS: The preclinical and epidemiological evidence regarding chemoprevention with selenium and vitamin E were reviewed. Secondary analyses from randomized trials of the 2 agents were included in the current analysis. Data from these analyses as well as evidence from the Prostate Cancer Prevention Trial were used to develop the SELECT schema. RESULTS: Preclinical, epidemiological and phase III data imply that selenium and vitamin E have potential efficacy for prostate cancer prevention. The experience of the Prostate Cancer Prevention Trial shows the interest and dedication of healthy men to long-term studies of cancer prevention. A total of 32,400 men are planned to be randomized in SELECT. CONCLUSIONS: SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment in the study is planned to begin in 2001 with final results anticipated in 2013.

SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design.

Prostate cancer is the commonest non-skin malignancy in the United States and has a substantial mortality rate despite the use of PSA-based screening. Furthermore, therapy for prostate cancer by surgery, radiotherapy or hormonal manipulation carries a significant risk of treatment-related morbidity. Recent analysis of secondary endpoints of several large-scale randomized prospective clinical trials for other malignancies has suggested that selenium or vitamin E may result in a decreased incidence and mortality from prostate cancer. In vitro and preclinical studies of these antioxidants support this hypothesis. This review outlines the rationale and design of SELECT, the Selenium and Vitamin E Cancer Prevention Trial, designed to test the hypothesis that selenium or vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population-based cohort of men at risk. SELECT is a phase III, randomized, double-blinded, prospective, 2x2 factorial clinical trial which will randomize 32,400 healthy men with normal DRE and serum PSA to one of four study arms: selenium alone, vitamin E alone, selenium+vitamin E, or placebo. Study agents will be taken orally for a minimum of 7 and maximum of 12 y with assessments of general health, incident prostate cancer and toxicity performed at 12 month intervals. Under the assumptions described, the detectable risk reduction is 25% for an effective single agent relative to placebo, with an additional 25% reduction for the combination relative to an effective single agent. The estimated power for the comparison of a single agent vs placebo is 96% and the power for the comparison of an effective single agent vs combination is 89%. Secondary endpoints will include prostate cancer-free survival, all-cause mortality, and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality of life assessments, assessment of serum micronutrient levels and prostate cancer risk, and studies of the evaluation of biological and genetic markers with the risk of prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 145-151

A randomized trial of two schedules of trimetrexate versus 5-fluorouracil in advanced colorectal cancer: a Southwest Oncology Group study.

Trimetrexate (TMQ), a non-classical folate antagonist, was studied in a randomized controlled trial in patients with advanced colorectal cancer and without prior chemotherapy. Patients were randomly assigned to one of three treatments: TMQ at 200 mg/m2 i.v. q 2 weeks, TMQ at 12 mg/m2 i.v. daily x 5 or 5-fluorouracil (5-FU) at 15 mg/kg i.v. weekly. Overall response rates were: 6% (four partial responses in 71 patients, 95% CI of 2-14%) for q 2 week TMQ, 0% (zero of 29, 95% CI of 0-29%) for daily x 5 TMQ and 18% (two complete and nine partial responses in 62 patients, 95% CI of 9-30%) for 5-FU. Median survival estimates were 10.3 months for the q 2 week TMQ schedule, 8.7 months for the daily x 5 TMQ schedule and 13.6 months for the 5-FU schedule. Grade < or = 3 toxicities were significantly more common with TMQ. TMQ does not appear to have significant antitumor activity against colorectal cancer.

Adjuvant chemotherapy for breast cancer: discordance between physicians' perception of benefit and the results of clinical trials.

PURPOSE: Decisions about management of patients depend on the perception of physicians about the results of clinical trials. We therefore determined whether physicians would recommend adjuvant chemotherapy for specified patients with breast cancer, and whether the perceived levels of benefit that led to these decisions were supported by the results of clinical trials. METHODS: We mailed a questionnaire that presented two clinical scenarios to 515 American and European oncologists. Scenario A depicted a premenopausal woman with node-negative, estrogen receptor-negative (ER-) breast cancer, and scenario B depicted a post-menopausal woman with node-positive, ER- disease. Respondents were asked about the evidence that they required from clinical trials to recommend adjuvant chemotherapy for these patients. RESULTS: Replies were received from 307 oncologists. American respondents were more likely to recommend adjuvant chemotherapy than Europeans (A, 93% v 68%; B, 85% v 67%; P < .001 for both comparisons). Opinion was evenly divided as to whether improvement in the relapse-free survival (RFS) rate was sufficient to recommend treatment, or whether improvement in overall survival was necessary. Mean values of 12.9% to 14.6% improvement in RFS at 3 years, or 10.7% to 12.4% improvement in overall survival at 5 years, were required to offer treatment. An overview analysis of clinical trials suggests that adjuvant chemotherapy achieves absolute improvements of 6% to 9% in RFS rates at 3 years and 3% to 4% in overall survival rates at 5 years for patients in these scenarios. CONCLUSIONS: Most oncologists recommended treatment in these scenarios, but require a level of treatment effect that has not been demonstrated in clinical trials. Our results suggest that oncologists' perceptions of the results of clinical trials overestimate the therapeutic gain from use of adjuvant chemotherapy for breast cancer.

Circulating group II phospholipase A2 activity and antilipocortin antibodies in systemic lupus erythematosus. Correlative study with disease activity.

OBJECTIVE: Lipocortin (LC) and phospholipase A2 (PLA2) are involved in phospholipid metabolism, and on the cellular level LC seems to be an antagonist of PLA2. Since anti-LC1 autoantibodies were found in systemic lupus erythematosus (SLE), we undertook a study of the relationship between PLA2, anti-LC1, and disease activity in a large group of patients with SLE. METHODS: Sera from 81 patients with SLE were tested for the activity of extracellular PLA2 and the presence and level of antilipocortin 1 [anti-LC1 (IgM) and anti-LC1 (IgG)] antibodies. Both were compared to SLE activity. RESULTS: Mean PLA2 activity was 4.6-fold higher in patients with SLE than in healthy controls (707 +/- 219 vs 154 +/- 6 u/ml, p < 0.01). PLA2 activity correlated significantly with PLA2 immunoreactivity as estimated by an ELISA method using monoclonal antibodies against "synovial type" PLA2 (n = 21, r = 0.984, p < 0.001). Anti-LC1 IgM and IgG antibody levels were significantly higher in SLE than in healthy individuals [anti-LC1 (IgM) 54.5 +/- 4.6 vs 22.6 +/- 2.3 EU/ml, p < 0.001 and anti-LC1 (IgG) 54.3 +/- 3.4 vs 22.9 +/- 2.3 EU/ml, p < 0.001]. There was no correlation between PLA2 activity and anti-LC1 antibody titers. Elevated levels of PLA2 [> normal mean + 2 SD (i.e., > 300 u/ml)] were found in 41/81 patients with SLE. Anti-LC1 antibody titers were high (> 64 EU/ml) in 23/41 patients; 14/40 patients with SLE with normal PLA2 (< 300 u/ml) also had higher titers of anti-LC1 antibodies. PLA2 activity was significantly associated with the presence of synovitis, being markedly increased in 11/12 patients. Mean PLA2 in this group of patients (1593 +/- 957 u/ml) was significantly higher (p < 0.001) than that (553 +/- 188 u/ml) in the group of 69 patients with SLE without synovitis. CONCLUSIONS: There was no correlation of PLA2 activity with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or the Lupus Activity Criteria Count (LACC). Circulating PLA2 activity in SLE correlated only with active synovitis. There was no correlation of anti-LC1 titers with duration of the disease, age, steroid dosage, SLEDAI, or LACC or any individual clinical or laboratory variable included in the assessment of SLEDAI and LACC.

Results of a policy of surveillance in stage I testicular seminoma.

PURPOSE: To determine what proportion of patients with Stage I testicular seminoma will be cured with orchidectomy alone. METHODS AND MATERIALS: From August 1984 to December 1991 148 patients with Stage I testicular seminoma were entered on a prospective study of surveillance following orchidectomy. The eligibility criteria included a normal chest X ray, lymphogram, computed tomography (CT) of the abdomen and pelvis, and normal post-orchidectomy tumor markers (AFP and BHCG). Patients were followed with a clinical assessment (markers, chest X ray and CT abdomen and pelvis) at 4 to 6 monthly intervals. RESULTS: With a median follow-up of 47 months (range 7-87 months), the actuarial relapse-free rate was 81% at 5 years. Twenty-three patients have relapsed with a median time to relapse of 15 months (range 2-61 months). Four patients (17%) relapsed at 4 or more years from diagnosis. Twenty-one of the 23 relapses occurred in the paraaortic lymph nodes, one patient relapsed in the mediastinum and ipsilateral inguinal nodes and one patient had an isolated ipsilateral inguinal node relapse. Nineteen patients were treated for relapse with external beam radiation therapy of which three developed a second relapse and were salvaged with chemotherapy. Four patients were treated for first relapse with chemotherapy and one developed a second relapse and died of disease. Age at diagnosis was the only prognostic factor for relapse, with patients age < or = 34 having an actuarial relapse-free rate at 5 years of 70% in contrast to a 91% relapse-free rate in those > 34 years of age. CONCLUSIONS: We recommend that surveillance in Stage I testicular seminoma should only be performed in a study setting until further data regarding the risk of late relapse and the efficacy of salvage chemotherapy is available.

Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study.

Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2 intravenously over one hour, on a daily x 5 schedule every 3 weeks. Toxicities of grade 3 or above included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0-9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.

Creation of a semiannual report for a multicentre co-operative clinical trials group.

The Southwest Oncology Group (SWOG) is a multicentre co-operative group that performs prospective clinical trials in cancer. The SWOG Statistical Center is responsible for preparing a report of studies for the semiannual meetings. The report includes a summary of study design and eligibility criteria, current accrual, baseline patient characteristics, toxicity, and, for studies closed to accrual and with sufficiently mature outcome data, tumour response or patient survival. A software program, Statisticians' Report Worksheet (SRW), has been developed by the programming staff at the SWOG Statistical Center. This program enables each disease specific chapter to be created independently, but ensures that tables and graphs for all chapters are of uniform style. We describe here the coordination of the report, and the use of the SRW program. This reporting system can serve as a model for other groups.

High incidence of coagualopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers.

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II trial of recombinant DNA gamma-interferon in advanced colorectal cancer: a Southwest Oncology Group study.

Fifty evaluable patients with advanced colorectal cancer, but without prior chemotherapy or immunotherapy, were randomized to one of two schedules of recombinant gamma-interferon (rGIFN). Twenty-four evaluable patients received rGIFN as a 2-h intravenous infusion daily x 5 every other week at a starting dose of 4.0 x 10(6) IU/m2/day (arm I). Twenty-six evaluable patients received rGIFN as a 24-h continuous intravenous infusion daily x 5 every month at a starting dose of 2.6 x 10(6) IU/m2/day (arm II). Toxicities on both schedules included flu-like symptoms, fevers/rigors, nausea/vomiting, hypotension, leukopenia, hepatotoxicity, nephrotoxicity, diarrhea, anemia, confusion, and ileus. Toxicity appeared to be more severe on arm I. No antitumor responses were observed, with 95% confidence intervals of 0 to 14% for arm I and 0 to 13% for arm II.

A phase II trial of recombinant tumor necrosis factor in patients with metastatic colorectal adenocarcinoma: a Southwest Oncology Group study.

Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 micrograms/m2/day as a 30-min i.v. infusion. One cycle consisted of 4 weeks of treatment over an 8-week period. Twenty-five patients have been entered into this study with three patients ineligible. The 22 eligible patients ranged in age from 38-73 years and had initial performance status of 0 in 10 patients, 1 in 10 patients, and 2 in 2 patients. No complete or partial responses were seen. Two patients had stable disease (no response) and 18 patients progressed. Two patients had no evaluation and were assumed to have had no response. The response rate is therefore 0%, with a 95% exact confidence interval of 0% to 15%. There was one grade 4 toxicity consisting of nausea and vomiting. Most common grade 3 toxicities were chills and fever in four patients, nausea and vomiting in three patients, and anemia and elevated liver enzymes in two patients. Headache, myalgia/arthralgia, and elevated serum triglycerides were frequently seen. Mildly elevated levels of fibrin split products were seen after TNF treatment in 5/13 evaluable patients and one ineligible patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II evaluation of recombinant gamma-interferon in patients with advanced pancreatic carcinoma: a Southwest Oncology Group study.

Thirty evaluable patients with advanced carcinoma of the pancreas received treatment with either daily x 5 bolus or continuous infusion x 5 days recombinant gamma-interferon. No responses were noted. Major toxicities included fever, hypotension, and flu-like symptoms. gamma-Interferon does not appear to be an active single agent for patients with advanced pancreatic cancer.