David L. Levin

Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial.

To describe the results of the first four rounds (T0‐T3) of prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial (designed to determine the value of screening in the four cancers), that for prostate cancer is evaluating whether annual screening with prostate‐specific antigen (PSA) and a digital rectal examination (DRE) reduces prostate cancer‐specific mortality.

Demographic characteristics of cancer of the pancreas: Mortality, incidence, and survival

Mortality and incidence rates for pancreatic cancer in the United States were examined by various demographic characteristics. Disease rates have continued to increase over time but at a much slower pace than in earlier years. Most recently available rates for blacks were significantly higher than for whites and rates for males of each race were higher than for females. Income and education levels had little influence on incidence rates among either blacks or whites. Incidence rates were not significantly higher in urban as compared with rural areas of Iowa and Colorado. The two‐year survival rate for pancreatic cancer was about 5% in recent years and did not vary significantly by race or sex. Smoking and diabetes, the two risk factors most consistently associated with the pancreatic cancer, explain only a small proportion of the disease. Much epidemiologic work remains to be done.

Primary management of advanced lymphosarcoma with radiotherapy

The results of a pilot study are described using radiotherapy as the primary treatment for patients with advanced lymphosarcoma. Therapy was directed toward the achievement of complete control of disease using total body irradiation (TBI) and total nodal irradiation (TNI). Chemotherapy had restricted use and was reserved for situations where further irradiation appeared to offer limited benefit. All 11 patients with generalized lymph node involvement (Stage III) are currently alive with a median observation of nearly 3 years, and 4 of these have remained continuously free of disease for more than 2 years since initial therapy. Encouraging remission and survival rates have also been observed for patients with generalized lymph node plus bone marrow involvement. In contrast, response to therapy and survival have been very unsatisfactory for patients with extranodal dissemination of disease to sites other than the bone marrow. The clinical staging has correlated better with survival than has the histologic classification based on estimation of tumor cell differentiation. This experience suggests a role for radiotherapy in the primary management of selected patients with advanced lymphosarcoma.

Trends in lung cancer. Mortality, Incidence, Diagnosis, Treatment, Smoking, and Urbanization

International trends in male lung cancer mortality rates have been rising but are beginning to level off. In the U.S., rates for men follow international trends; rates for women are increasing at a greater than exponential pace and far more rapidly than for men. Rates for non‐whites are rising faster than for whites. The trends in smoking (as a measure of personal air pollution)—increasing for women, decreasing for men—and urbanization (as an indirect measure of non‐personal air pollution)—higher for non‐whites than for whites—are correlated with cancer trends. There is evidence that several lung cancer hazards operating together multiply the risks. Patterns in diagnosis and survival are discussed, and recommendations are made for future study and action to reduce lung cancer mortality.

Cancer of the pancreas. Available epidemiologic information and its implications

Cancer of the pancreas is the fourth leading cause of death among all sites of cancer in the United States. Very little is known about the epidemiology of the disease. Available data on incidence and mortality are examined to determine epidemiologic patterns. Racial differences in incidence/mortality data and their relation to industrial hazards, quality of medical care, and geographic distribution of cancer are discussed. The need for more definitive studies is noted, and suggestions for areas of future work are made.

Prostate Specific Antigen Changes as Related to the Initial Prostate Specific Antigen: Data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

PURPOSE Annual screening with PSA, although of unproven benefit, is currently used for prostate cancer early detection. A large fraction of screened men have low (less than 2 ng/ml) initial PSA. The yield over time of positive PSA screens (ie more than 4 ng/ml) in these men has not been well characterized in large cohorts in the United States. MATERIALS AND METHODS Men in the screening arm of the PLCO received baseline PSA and annual tests for 5 years. 30,495 of these men had baseline PSA 4 ng/ml or less. We estimated the cumulative probability of converting to PSA greater than 4 at years 1 through 5 as a function of baseline PSA. RESULTS Among men with baseline PSA less than 1 ng/ml, 1.5% converted by year 5 (95% CI 1.2-1.7). Among men with baseline PSA of 1.0 to 1.99 ng/ml, 1.2% (95% CI 0.9-1.3) and 7.4% (95% CI 6.8-8.1) converted by year 1 and 5, respectively. A total of 33.5% and 79% of men with initial PSA of 2.0 to 2.99 and 3.0 to 4.0, respectively, converted by year 5. Of men with baseline PSA less than 1 ng/ml converting to PSA more than 4 ng/ml, 8% were diagnosed with cancer within 2 years of conversion. About 10% of men with baseline PSA less than 1 ng/ml and negative baseline DRE had a positive DRE within 3 years. CONCLUSIONS For men choosing PSA screening, screening every 5 years for baseline PSA less than 1 ng/ml and every 2 years for PSA 1 to 2 ng/ml could result in a 50% reduction in PSA tests and in less than 1.5% of men missing earlier positive screens, but with an unknown effect on prostate cancer mortality.

RELATIONSHIP OF DEMOGRAPHIC AND CLINICAL FACTORS TO FREE AND TOTAL PROSTATE-SPECIFIC ANTIGEN

OBJECTIVES To characterize the role of demographic and clinical parameters in the measurements of prostate-specific antigen (PSA), free PSA (fPSA), and percent free PSA (%fPSA). METHODS This was a cohort study of volunteers to a randomized screening trial. A central laboratory determined PSA and fPSA for the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. A baseline evaluation of free and total PSA was done for 7183 white, black, Asian, Hispanic, and other male volunteers, aged 55 to 74 years. Comparisons were made across racial and ethnic groups and across a set of clinical parameters from a baseline questionnaire. RESULTS The median levels of serum PSA were less than 2.1 ng/mL in each age-race grouping of the study participants. The levels of free and total PSA were higher in black (n = 868, 12%) participants than in white (n = 4995, 70%) and Asian (n = 849, 11.8%) participants. Individuals who identified themselves as ethnically Hispanic (n = 339, 4.7%) had median PSA levels higher than whites who were not Hispanic. The free and total PSA levels increased with age, particularly among men 70 to 74 years old. However, the %fPSA levels showed less variation among the four racial groups or by age. The free and total PSA levels were higher among those who had a history of benign prostatic disease. CONCLUSIONS Demographic (age and race/ethnicity) and clinical (history of benign prostatic disease) variables had a moderate effect on the measures of PSA and fPSA and very little effect on %fPSA.

Coordination and management of a large multicenter screening trial: The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large and complex multi-institutional, multifaceted organization with a 20-year horizon. The implementation of the trial began with the creation of an organizational structure that supports strong leadership, cooperation, and effective communication among the trial collaborators including an operational framework for the development, review, and pretest of instruments, data collection, and management procedures; the setting of high-quality standards for training of trial staff; and the development of a comprehensive assessment plan for evaluation of all trial activities. This paper describes the process and methods used in the coordination and management of the PLCO trial. These include the role of the steering committee and its subcommittees and working groups, the establishment of regular and ad hoc communications among collaborators, the training of screening center coordinators and examiners, the PLCO manual of operations and procedures, and the development and implementation of a comprehensive quality assurance plan.

Breast cancer skin test antigens of increased sensitivity prepared from vesicular stomatitis virus‐infected tumor cells

Crude membrane (CM) extracts were prepared from five cultured breast tumor lines (MDA‐MB‐157, MDA‐MB‐231, ZR75‐1, HS0578T, and MCF‐7) which had been infected with vesicular stomatitis virus (VSV) to augment their antigenicity. In skin test trials, CM extracts of uninfected MCF‐7 cells elicited positive responses in 0 of 13 (0%) tests in breast cancer patients, while VSV‐MCF‐7 elicited positive responses in 11 of the same 13 patients (84.6%). CM extracts of VSV‐ZR75‐1 and VSV‐MCF‐7 elicited greater delayed hypersensitivity responses (mm induration at 48 hr) in breast cancer patients than in patients with lung carcinoma or melanoma. Although the sensitivity of VSV‐ZR75‐1 was too low (ten of 28, or 35.7%, of tests positive) to be useful as a skin test antigen, VSV‐MCF‐7 elicited positive responses in 30 of 38 (78.9%) tests in breast cancer patients, as compared to two of 15 (13.3%) and two of 13 (15.4%) of tests in patients with lung carcinoma and melanoma, respectively. The “virus‐augmented” CM extract of cultured MCF‐7 cells exhibited markedly greater sensitivity as compared to control MCF‐7 extracts (P < .005), with a high degree of specificity for breast cancer patients as compared to patients with the other neoplasms (P < .00001). The results of skin testing with VSV‐MCF‐7 CM extracts demonstrated antigenic cross‐reactivity with a large number of breast cancer patients, a finding of great importance for any potential immunotherapy and/or immunodiagnosis.