By Demetrios Tzimas, MD
Faculty Peer Reviewed
In our last Primecuts, Dr. Mathew Robinson reported on the U.S. Preventive Services Task Force’s new recommendation against measuring prostate specific antigen (PSA) as a method of screening for prostate cancer. This week, prostate cancer has made it back into the headlines. JAMA reports on some concerning findings in an extended follow-up of the original Selenium and Vitamin E Cancer Prevention Trial (SELECT). The original trial was initiated because of prior retrospective evidence that Selenium and Vitamin E may reduce prostate cancer risk. 35,533 healthy men at average risk of prostate cancer aged 50 and older with normal PSA values and normal digital rectal exams were randomized into four groups: Selenium (200 micrograms daily) with placebo, Vitamin E (400 International Units daily) with placebo, Selenium and Vitamin E, and two placebo’s. Patients were followed from 2001 to 2008. The study was stopped in 2008 as there was a lack of efficacy for risk reduction and the supplementation was discontinued. Yet, on review of the data, there was concern from the safety committee that there was an increased risk of prostate cancer in the Vitamin E/placebo group that approached statistical significance. Thus, participant follow up continued in an unblinded fashion from 2008 to 2011. When re-analyzing the results, there were 529 cases of prostate cancer in the placebo group, 575 in the Selenium group, 555 in the Selenium/Vitamin E group (all differences of which were not statistically significant), but there was a statistically significant increase in the incidence of prostate cancer in the Vitamin E group, with 620 cases over the 10 year time period. The authors claim that this finding was not an effect of “digging through the data,” as this trend was apparent in the original publication, and bore out significance when including a longer follow-up. Although a biological explanation for why Vitamin E increases the risk of prostate cancer was not studied or even postulated, a few important lessons can be learned from this trial. Although supplementation with macro/micro nutrients is commonplace, many of these have U shaped curves of benefits, and over-supplementation may lead to harm. While long-term follow-up is difficult in large scale trials, errors in analysis could prove fatal for many patients especially if poor outcomes are not captured. [1]
A large phase III trial of a malaria vaccine also made major headlines this week. Authors of this trial, published in the New England Journal of Medicine are studying the RTS,S/AS01 vaccine in children. This vaccine targets the circumsporozoite protein of Plasmodium falciparum. The primary endpoint of efficacy for this trial was defined as fever greater than 37.5 Celsius with P. falciparum parasitemia twelve months after the vaccine series was given. The trial is studying two cohorts of children (6-12 weeks of age and 5-17 months of age) each split into three groups: 3 doses of RTS,S/AS01 one month apart with booster after 3rd dose, 3 doses without a booster, and non-malaria vaccines as placebo arms (rabies vaccine for older cohort and meningococcal vaccine for younger cohort). This phase III publication only reports data on the older cohort of children, a group of 8,923 total participants. During the 12 month follow-up period, the per person-year rate of malaria was 0.44 in the RTS,S/ASO1 group versus 0.83 in the control group, a statistically significant efficacy of 55.8% for the vaccine. Although these results are very encouraging, several more years of data and follow-up are needed to determine the safety and the long-term efficacy of this vaccine for high risk African children who are currently at great danger of morbidity and mortality from this disease. Also, when the trial is finally completed, a keen eye needs to look into the data as it is partially funded by GlaxoSmithKline Biologicals. [2]
Also in The New England Journal of Medicine is a study that evaluates the incidence of adenocarcinoma in patients diagnosed with Barrett’s Esophagus. It is well known that intestinal metaplasia in the distal esophagus (Barrett’s Esophagus) is a precursor lesion to esophageal adenocarcinoma,. Since over time dysplasia of the epithelium leads to adenocarcinoma, surveillance programs using esophagogastroduodenoscopy have been instituted to monitor progression. Surprisingly though, 95% of patients with a new diagnosis of adenocarcinoma do not have a prior diagnosis of Barrett’s Esophagus. Further, the authors point out that surveillance programs have not shown to have an effect on survival. As such, the aim of the study was to calculate the incidence of adenocarcinoma among patients with Barrett’s Esophagus compared to that of the general population, and determine whether low grade dysplasia is a true risk factor for adenocarcinoma. The researchers used a pathology registry to identify all patients who received a diagnosis of Barrett’s Esophagus, low grade dysplasia, high grade dysplasia, and adenocarcinoma, and followed up patients with these diagnoses from 1992 to 2009. In their findings, the overall annual incidence rate of adenocarcinoma after an initial diagnosis of Barrett’s Esophagus without dysplasia was 0.12% as compared to 0.03% in those diagnosed without an initial diagnosis of Barrett’s in the general population. They did find a relative risk of 5.1 of developing adenocarcinoma in patients who were diagnosed with Barrett’s and had low grade dysplasia at initial endoscopy. Despite this increased risk, the authors concluded that their study “provides solid evidence that esophageal adenocarcinoma will develop in very few patients with Barrett’s esophagus…routine surveillance of such patients (without dysplasia) is of doubtful value.” The authors thus note that the current surveillance guidelines (endoscopy every three years for Barrett’s, yearly for low grade dysplasia, every 3 months for high grade [3]) are based off of previous studies show that after being diagnosed with Barrett’s the incidence of adenocarcinoma is approximately four to five times higher than that found in this data set. The authors further note that these studies were severely flawed as they only had a few hundred patients, had shorter follow-up periods, and had a great deal of loss to follow-up. They thus call into question the rationale for ongoing surveillance, despite the fact that there still was a higher incidence rate of adenocarcinoma with Barrett’s Esophagus. Although this is a bold statement and contradicts the current guidelines, this type of surveillance is indeed very controversial, as there are no randomized controlled trials to prove its efficacy. [4]
From the distal esophagus up to the heart, a recent trial published the Annals of Internal Medicine demonstrates the benefits of Colchicine for Recurrent Pericarditis (CORP). The CORP Trial enrolled 120 patients with a first recurrence of pericarditis (without bacterial or neoplastic causes) and randomly assigned them to a placebo pill or colchicine (1 to 2mg based on renal function and tolerance on the first day, followed by a maintenance dose of 0.5 to 1mg every 12 hours for 6 months), along with the conventional treatment of a non-steroidal antinflammatory drug (NSAID) tapered over a month. The primary endpoint was the recurrence rate at 18 months. Follow-up visits occurred at one week, and at 1,3,6,12, and 18 months with EKG, Echocardiogram, and blood chemistries performed to monitor for recurrence. There was a 55% rate of recurrence in the placebo/conventional treatment group, and a 24% rate of recurrence in the colchicine/conventional treatment group; these differences were statistically significant. Surprisingly, the side effect profile was not different between colchicines and placebo. While the exact mechanism is not fully understood, it is thought that by disrupting microtubules, colchicine may inhibit leukocyte function and therefore reduce inflammation. Although colchicine is not currently approved by the FDA in the United States for the prevention of pericarditis, the small side effect profile should promote the continued off label use of this drug. [5]
Still on the heart, the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) group published in Circulation this week a post hoc analysis of their large database that examined the cardiovascular benefits associated with strict blood pressure targets in patients with high risk cardiovascular disease. Hypertensive guidelines currently recommend a goal of less than 140/90mm Hg in the general population, but to less than 130/80 in those of high cardiovascular risk (renal disease, diabetes, prior cardiovascular event). Authors of this study noted that in the ACCORD Trial, overall risk of cardiovascular events in diabetic patients was similar in patients randomized to a goal of less than 140mm Hg or less than 120mm Hg, but that the side effects were greater in the 120mm Hg group. The ONTARGET study was a multicenter trial that randomized 31,546 patients with known atherosclerotic disease or diabetes to telmisartan 80mg once daily, ramipril 10mg once daily, or both. The primary endpoint of the trial was the composite outcome of death resulting from cardiovascular causes. In this current re-analysis of the data, patients were grouped into the percentages of time that they achieved goal blood pressure measurements at their various visits (less than 25% of the time, 25-49%,50-74% and greater than 75% of the time). The rates of cardiovascular events were compared between those who reached their goals of less than 140/90 greater than 75% of the time against those who did not meet them as often, and between those reaching their goals of less than 130/80 greater than 75% of the time against those who did not meet them as often (ie. less than 75% of the time). Results demonstrated a significant decrease in death from cardiovascular causes in those achieving a blood pressure of less than 140/90 75% of the time, but no more benefit when patients reached a blood pressure of less than 130/80 75% of the time. The authors conclude that in high risk cardiovascular patients a blood pressure reduction to less than 140/90 is associated with protection, although this is not improved by even lower blood pressure targets as recommended in most current guidelines. It must be emphasized that this study is a post hoc analysis of a trial that was comparing the effects of an angiotensin converting enzyme inhibitor against an angiotensin receptor blocker, and while the data are intriguing, they should not alter the current recommendations, but spur further studies that specifically target this particular question. [6]
Dr. Demetrios Tzimas is a contributing editor, Clinical Correlations and a 3rd year resident at NYU Langone Medical Center
Peer reviewed by Neil Shapiro, MD, Editior-In-Chief, Clinical Correlations
Image courtesy of Wikimedia Commons
References:
- Klein E, Thompson I, Tangen C, et al. Vitamin E and the Risk of Prostate Cancer. Journal of the American Medical Association. 2011; 306 (14): 1549-1556. Available from http://jama.ama-assn.org/content/306/14/1549.full
- RTS,S Clinical Trials Partnership. First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children. The New England Journal of Medicine. Forthcoming 2011. Available from http://www.nejm.org/doi/full/10.1056/NEJMoa1102287#t=article
- Wang K, Sampliner R. Updated Guidelines 2008 for the Diagnosis, Surveillance, and Therapy of Barrett’s Esophagus. American Journal of Gastroenterology. 2008; 103: 788-797. Available from http://www.nature.com.ezproxy.med.nyu.edu/ajg/journal/v103/n3/full/ajg200850151a.html
- Hvid-Jensen F, Pedersen L, Drewes A, et al. Incidence of Adenocarcinoma among Patients with Barrett’s Esophagus. The New England Journal of Medicine. 2011; 365:1375-1383. Available from http://www.nejm.org/doi/full/10.1056/NEJMoa1103042#t=article
- Imazio M, Brucato A, Cemin R, et al. Colchicine for Recurrent Pericarditis. Annals of Internal Medicine. 2011; 155: 409-414. Available from http://www.annals.org/content/early/2011/08/26/0003-4819-155-7-201110040-00359.full
- Mancia G, Schumacher H, Redon J, et al. Blood Pressure Targets Recommended by Guidelines and Incidence of Cardiovascular and Renal Events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET). Circulation. 2011; 124: 1727-1736. Available from http://http://circ.ahajournals.org.ezproxy.med.nyu.edu/content/124/16/1727.full