Paul F. Pinsky

Public Health Service Study on Reye's Syndrome and Medications Report of the Pilot Phase

Between February and May 1984, we conducted a pilot study to examine the methods for a larger study of a previously reported relation between Reyes syndrome and medications. Thirty patients with Reyes syndrome, whose diagnosis was confirmed by an expert panel, and 145 controls were matched for age, race (black or not black), and antecedent illness (respiratory infection, chickenpox, or diarrhea) and selected from the same hospital, emergency room, or school, or identified by random digit dialing. Significantly more cases (93 per cent, 28 of 30) than members of each of the four control groups or all controls combined (46 per cent, 66 of 145) had received salicylates during matched antecedent illnesses (odds ratio of all 30 cases vs. all controls = 16.1; lower 95 per cent confidence limit = 4.6). The prevalence and mean severity score of signs, symptoms, and selected events during the antecedent illness tended to be lower among cases than controls. Thus, differences in the severity of this illness between cases and controls did not explain differences in medication exposures. This pilot study suggests an association between Reyes syndrome and the use of salicylates during an antecedent illness.

Prostate Cancer Screening — A Perspective on the Current State of the Evidence

Controversy continues to roil around the role of PSA screening in prostate cancer. The authors review the available data and its quality and conclude that the evidence does not indicate that the benefits outweigh the harms.

Association of Colonoscopy Adenoma Findings With Long-term Colorectal Cancer Incidence

Importance Individuals with adenomatous polyps are advised to undergo repeated colonoscopy surveillance to prevent subsequent colorectal cancer (CRC), but the relationship between adenomas at colonoscopy and long-term CRC incidence is unclear. Objective To compare long-term CRC incidence by colonoscopy adenoma findings. Design, Setting, and Participants Multicenter, prospective cohort study of participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer randomized clinical trial of flexible sigmoidoscopy (FSG) beginning in 1993 with follow-up for CRC incidence to 2013 across the United States. Participants included 154 900 men and women aged 55 to 74 years enrolled in PLCO of whom 15 935 underwent colonoscopy following their first positive FSG screening result. The final day of follow-up was December 31, 2013. Exposures Enrolled participants had been randomized to FSG or usual care. Participants who underwent FSG and had abnormal findings were referred for follow-up. Subsequent colonoscopy findings were categorized as advanced adenoma (≥1 cm, high-grade dysplasia, or tubulovillous or villous histology), nonadvanced adenoma (<1 cm without advanced histology), or no adenoma. Main Outcomes and Measures The primary outcome was CRC incidence within 15 years of the baseline colonoscopy. The secondary outcome was CRC mortality. Results There were 15 935 participants who underwent colonoscopy (men, 59.7%; white, 90.7%; median age, 64 y [IQR, 61-68]). On initial colonoscopy, 2882 participants (18.1%) had an advanced adenoma, 5068 participants (31.8%) had a nonadvanced adenoma, and 7985 participants (50.1%) had no adenoma; median follow-up for CRC incidence was 12.9 years. CRC incidence rates per 10 000 person-years of observation were 20.0 (95% CI, 15.3-24.7; n = 70) for advanced adenoma, 9.1 (95% CI, 6.7-11.5; n = 55) for nonadvanced adenoma, and 7.5 (95% CI, 5.8-9.7; n = 71) for no adenoma. Participants with advanced adenoma were significantly more likely to develop CRC compared with participants with no adenoma (rate ratio [RR], 2.7 [95% CI, 1.9-3.7]; P < .001). There was no significant difference in CRC risk between participants with nonadvanced adenoma compared with no adenoma (RR, 1.2 [95% CI, 0.8-1.7]; P = .30). Compared with participants with no adenoma, those with advanced adenoma were at significantly increased risk of CRC death (RR, 2.6 [95% CI, 1.2-5.7], P = .01), but mortality risk in participants with nonadvanced adenoma was not significantly different (RR, 1.2 [95% CI, 0.5-2.7], P = .68). Conclusions and Relevance Over a median of 13 years of follow-up, participants with an advanced adenoma at diagnostic colonoscopy prompted by a positive flexible sigmoidoscopy result were at significantly increased risk of developing colorectal cancer compared with those with no adenoma. Identification of nonadvanced adenoma may not be associated with increased colorectal cancer risk. Trial Registration clinicaltrials.gov Identifier: NCT00002540

The bimanual ovarian palpation examination in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: Performance and complications:

Objective To provide evidence about the performance characteristics and consequences of bimanual ovarian palpation. Setting and methods The Prostate, Lung, Colorectal and Ovarian cancer screening trial randomized 154,900 individuals to either an intervention or control arm. Enrolled eligible participants were aged 55–74, had no history of trial cancers, and no current treatment for cancer. Intervention arm women received CA-125 tests and transvaginal ultrasound. Bimanual ovarian palpation was offered annually during the first four years of the trial. Bimanual ovarian palpation-specific sensitivity and specificity were calculated, as were rates of diagnostic procedures and resulting complications following positive bimanual ovarian palpation screens. Results A total of 20,872 women received at least one bimanual ovarian palpation, with 50,498 total bimanual ovarian palpation examinations performed. The sensitivity and specificity of bimanual ovarian palpation were 5.1% (2/39) and 99.0% (49,957/50,459), respectively; no cases were detected by bimanual ovarian palpation alone. Rates for most follow-up procedures for abnormal results in women without ovarian cancer were higher among the group with another screening test positive, except for pelvic exam, where rates were similar. No complications were reported in the bimanual ovarian palpation-only positive group. Conclusion Low sensitivity of bimanual ovarian palpation alone and in combination with other tests argue against using bimanual ovarian palpation as a screening test for ovarian cancer in asymptomatic women.

Secondary prostate cancer screening outcomes by race in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial

Despite disparities in prostate cancer incidence and mortality rates between black and white men, there is still insufficient data available to assess potential differences in the benefits and harms of prostate cancer screening by race. Although the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial is underpowered to detect a difference by race in prostate‐cancer specific mortality, because of the large study size, there are still sufficient numbers to examine secondary screening outcomes. The objective of this analysis is to examine whether differences exist between black and white participants with respect to screening false‐positive rates, biopsy follow‐up of men with positive screens, tumor characteristics, and overdiagnosis of prostate cancer.

Incidental renal tumours on low-dose CT lung cancer screening exams

Introduction Renal cancer incidence has increased markedly in the United States in recent decades, largely due to incidentally detected tumours from computed tomography imaging. Here, we analyze the potential for low-dose computed tomography lung cancer screening to detect renal cancer. Methods The National Lung Screening Trial randomized subjects to three annual screens with either low-dose computed tomography or chest X-ray. Eligibility criteria included 30 + pack-years, current smoking or quit within 15 years, and age 55–74. Subjects were followed for seven years. Low-dose computed tomography screening forms collected information on lung cancer and non-lung cancer abnormalities, including abnormalities below the diaphragm. A reader study was performed on a sample of National Lung Screening Trial low-dose computed tomography images assessing presence of abnormalities below the diaphragms and abnormalities suspicious for renal cancer. Results There were 26,722 and 26,732 subjects enrolled in the low-dose computed tomography and chest X-ray arms, respectively, and there were 104 and 85 renal cancer cases diagnosed, respectively (relative risk = 1.22, 95% CI: 0.9–1.5). From 75,126 low-dose computed tomography screens, there were 46 renal cancer diagnoses within one year. Abnormalities below the diaphragm rates were 39.1% in screens with renal cancer versus 4.1% in screens without (P < 0.001). Cases with abnormalities below the diaphragms had shorter median time to diagnosis than those without (71 vs. 160 days, P = 0.004). In the reader study, 64% of renal cancer cases versus 13% of non-cases had abnormalities below the diaphragms; 55% of cases and 0.8% of non-cases had a finding suspicious for renal cancer (P < 0.001). Conclusion Low-dose computed tomography screens can potentially detect renal cancers. The benefits to harms tradeoff of incidental detection of renal tumours on low-dose computed tomography is unknown.

Lung Cancer Mortality in the Lung Screening Study Feasibility Trial

Abstract The Lung Screening Study was a multicenter controlled feasibility trial that randomly assigned subjects to undergo two rounds of screening with either low-dose spiral computed tomography (LDCT) or chest X-ray (CXR). Long-term follow-up was performed to evaluate any differences in lung-cancer-specific and all-cause mortality between arms. In 2000, subjects were randomly assigned at six screening centers. Linkage with the National Death Index was performed to ascertain long-term mortality for subjects. Median follow-up for mortality of the 1660 and 1658 subjects randomly assigned to LDCT and CXR, respectively, was 5.2 years. There were 32 and 26 deaths from lung cancer in the two groups, respectively, corresponding to lung cancer death rates of 3.84 and 3.10 per 1000 person-years, and a risk ratio of 1.24 (95% confidence interval = 0.74 to 2.08). The risk ratio for all-cause mortality was 1.20 (95% confidence interval = 0.94 to 1.54). These findings can contribute to the overall knowledge on LDCT lung cancer screening.

Abstract B034: Time to treatment and overall survival among men with localized prostate cancer

Background: Prostate cancer is the second most common cancer diagnosed among men in the United States. Delays from the time of confirmed diagnosis to primary treatment are more common for prostate compared to other malignancies. The objective of this study was to investigate factors associated with time to treatment and the effect of time to treatment on overall survival among men with early-stage prostate cancer. Methods: From the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, men diagnosed with localized prostate cancer who received treatment within a year of diagnosis were selected for analysis (N=6,349). Selected men had date of diagnosis, treatment date, and mortality status as of 2012. We investigated sociodemographic and clinical factors associated with time to treatment using Cox regression. We also used Cox regression to examine the effect of time to treatment on overall survival. Covariates included Gleason score, PSA level, age at diagnosis, employment status, education level, race, marital status, and comorbidity burden. Results: The median time to treatment was 73 (IQR: 44-120) days. Demographic factors associated with longer time to treatment included being Black (adjusted hazard ratio (aHR)= 0.85, 95%CI: 0.76-0.95), having some college education (aHR= 0.91, 95%CI: 0.85-0.97), and having a baccalaureate degree or a post-baccalaureate degree (aHR= 0.89, 95% CI: 0.84-0.95). Clinical factors associated with longer time to treatment were being diagnosed at an older age (aHR= 0.86, 95%CI:0.80-0.93 for age of 70-74 years and aHR= 0.80, 95%CI: 0.74-0.87 for 75 year and older) and having an elevated PSA level (HR=0.89, 95%CI: 0.81-0.94 for third PSA quartile (6.11-9.0) and HR=0.87, 95%CI: 0.81-0.94 for fourth PSA quartile (9.0 and above). Gleason score and comorbidity burden were not associated with time to treatment. Being married (aHR=1.11, 95%CI: 1.03-1.19) and being retired (aHR=1.09, 95%CI:1.034-1.16) were associated with shorter time to treatment. After adjusting for sociodemographic and clinical characteristics, time to treatment did not have a significant effect on overall survival. Conclusions: College education, being Black, older age at diagnosis, and higher PSA levels were associated with longer time to treatment. Being married and being retired were associated with shorter time to treatment. Longer time to treatment was not associated with overall mortality among PLCO men with localized prostate cancer. Citation Format: Dudith Pierre-Victor, Paul Pinsky, Iman K. Martin, Worta McCaskill-Stevens. Time to treatment and overall survival among men with localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B034.

Data sharing in clinical trials: An experience with two large cancer screening trials

Paul Pinsky of the US National Cancer Institute and colleagues describe the implementation and outcomes of web-based data sharing from the PLCO and NLST cancer screening trials.

Colorectal Cancer Screening

absent data are likely missing at random. When comparing questionnaire and medical record information regarding number of IVF cycles among women with both sources (n = 9769 [51%]), 80% of women were classified into the same category. Therefore, it is unlikely that using self-reported subfertility diagnosis and number of cycles for 23% would have biased the results. Tomao and colleagues suggest that it would be interesting to investigate whether ovarian stimulation for IVF can promote the occurrence of biologically different types of breast cancer, as in the case of tamoxifen-related endometrial cancer. We agree this would be interesting; however, because IVF treatment was not associated with increased risk of breast cancer, we considered it less relevant to examine whether IVF treatment was associated with breast cancer type. To investigate whether exposure to many IVF cycles could be associated with decreased risk of specific breast cancer types, larger numbers of women with breast cancer would be needed. We agree that the decreased breast cancer risk in women treated with many IVF cycles (≥7 compared with 1-2) might also be associated with the improvement of ovarian function after repeated endocrine stimulations, or there could be other possible explanations. In the analyses, we adjusted for parity and age at first birth as clinical outcomes of IVF, which were the only confounding factors. Other clinical outcomes (ie, cancelled cycles, ovarian hyperstimulation syndrome, poor response to first IVF cycle, and duration of gestation <24 weeks) did not influence the results. However, we did not have measures of estradiol and progesterone levels to draw definitive conclusions. In our study, infertility and infertility-related nulliparity were not associated with increased risk of breast cancer. We think that anovulatory or poor ovulatory cycles should be treated to restore normal ovarian activity if women wish to have a child or are hindered by their irregular ovulatory cycles, regardless of a potential reduction of breast cancer risk.