Can prostate-specific-antigen, or PSA, screening for prostate cancer be cost-effective? A study led by Fred Hutch biostatistician Dr. Ruth Etzioni and health economist Dr. Joshua Roth, published yesterday in JAMA Oncology, examines that question.
The future of PSA screening is uncertain, with the U.S. Preventive Services Task Force’s recommendation against routine screening for prostate cancer and conservative guidance from other panels.
Etzioni, Roth and colleagues used simulation modeling to examine the potential cost-effectiveness of various plausible PSA screening strategies and to assess the value added by increased use of conservative management among low-risk, screening-detected cancer cases.
The study found that if PSA screening is to be cost-effective, it should be used conservatively, every four years, and only in men between the ages of 55 and 69. Biopsy referrals should be restricted to those with very high PSA levels.
However, under selective treatment for men with low-risk disease, the investigators found that screening could be cost-effective using standard PSA thresholds for biopsy referral.
For the study, low-risk disease was defined as indolent, non-aggressive tumors (those with a Gleason score lower than 7 and a clinical stage of T2a or lower). Selective treatment was defined as taking a “watchful waiting” approach, also known as active surveillance, and treating the cancer only after evidence of disease progression, such as a spike in PSA levels or other indications of clinically significant tumor activity.
“The study provides, to our knowledge, the first quantitative framework to evaluate the comparative effectiveness of PSA-based screening strategies and selective treatment approaches, and it addresses an urgent need for direction concerning the future of PSA screening in the United States,” the authors wrote.
Etzioni and colleagues went on to write: “Rather than stopping PSA screening, as recommended by the U.S. Preventive Services Task Force, implementation of strategies that extend the screening interval and/or use higher PSA biopsy thresholds have the potential to preserve substantial benefit while controlling harm and costs.”
Costs include not only the costs of the PSA test, Etzioni said, but the costs of any false-positive biopsies and “overdiagnosed” cases in which men with indolent tumors are treated unnecessarily.
The bottom line, Etzioni said, is for patients to ask themselves whether they can choose to forego treatment if diagnosed with a low-risk cancer and for physicians to ask themselves whether they can decide against recommending treatment for patients with non-aggressive tumors.
“I feel that if the answer to this question is no, then it may be prudent to think twice before screening,” Etzioni said. “I hope that physicians will recognize that they have to be either very conservative in their screening practice or very conservative in their treatment recommendations. It is not cost-effective for us to be screening and treating [low-risk prostate cancer] aggressively.”
The National Cancer Institute, the Centers for Disease Control and Prevention (as part of the Cancer Intervention and Surveillance Modeling Network) and the Agency for Healthcare Research and Quality funded the research.
Fred Hutch biostatistician Dr. Roman Gulati was instrumental in analysis and quality assurance for this study, Etzioni said.
Kristen Woodward / Fred Hutch News Service
Drs. Soheil Meshinchi and Marie Bleakley, both pediatric oncology physician-scientists in Fred Hutch’s Clinical Research Division, this week received a $1 million Quantum Award Grant from Hyundai Hope on Wheels, a nonprofit organization dedicated to helping kids fight cancer. They will receive $250,000 per year over four years to fund their research on acute myeloid leukemia, or AML.
Specifically, they will focus on the discovery of molecules that can serve as optimal targets for T-cell-based immunotherapy that attacks AML cells while sparing healthy tissue. To this end they will use state-of-the-art genetic sequencing technologies and samples from nearly 1,000 pediatric AML patients to discover new leukemia-specific genetic variants to serve as T-cell targets.
“We have made enormous progress in treating children with acute myeloid leukemia,” Bleakley said. “However, today’s highly toxic therapies, including blood stem cell transplantation, can cause dangerous side effects and do not always cure leukemia. Too many patients still relapse and die from their disease. There is an urgent need for less toxic and more effective therapies.”
Their award-winning AML research is also featured in this Hyundai Hope on Wheels video.
Other Children’s Oncology Group institutions that received $1 million Hyundai Quantum Award grants this week were Children’s Hospital of Philadelphia, Dana-Farber Cancer Institute and the University of Florida.
The winners were recognized yesterday at the annual Hyundai Hope On Wheels ceremony in New York City. The event marked the organization’s 18 years of commitment to the cause and a total of $115 million donated in its pledge to end childhood cancer. This year alone, the organization will award $13 million in new pediatric cancer research grants.
Kristen Woodward / Fred Hutch News Service
Smoking increases an individual’s risk of developing tuberculosis – and makes the infection worse — because it causes vital immune cells to become clogged up, slowing their movement and impeding their ability to fight infection, according to new research published yesterday in the journal Cell.
Dr. Cecilia Moens, a developmental biologist and member of the Fred Hutch Basic Sciences Division, was a collaborator on the study, which was conducted by an international team of researchers led by the investigators at the University of Cambridge and the University of Washington.
TB is an infectious disease caused by Mycobacterium tuberculosis that primarily infects the lungs, but it can also infect other organs. It is transmitted from person to person through the air. The disease can cause breathlessness, wasting, and eventual death. While treatments do exist, the drug regimen is one of the longest for any curable disease: a patient will typically need to take medication for six months.
For people exposed to TB, the biggest risk factor for infection is exposure to smoke, including active and passive cigarette smoking and smoke from burning fuels. However, until now it has been unclear why smoke should increase this risk.
When TB enters the body, the first line of defense it encounters is a specialist immune cell known as a macrophage (Greek for “big eater”). This cell engulfs the bacterium and tries to break it down. In many cases, the macrophage is successful and kills the bacterium, preventing TB infection, but in some cases TB manages not just to avoid destruction, but to use macrophages as vehicles to travel deep into the host, spreading the infection. TB’s next step is to cause infected macrophages to form tightly organized clusters known as tubercles, or granulomas. At this point, the macrophages and bacteria fight a battle — if the macrophages lose, the bacteria use their advantage to spread from cell to cell.
Moens and colleague Dr. Lalita Ramakrishan from the Department of Medicine at the University of Cambridge, who led the study, collaborated several years ago on a genetic screen in zebrafish — a “see-through” animal model for studying TB — to identify mutants that were predisposed to TB infection.
“The mutant that is the subject of this paper, found in a gene called snapc1, came out of that screen,” Moens said.
Together they identified a variant linked to lysosomal deficiency disorders. The lysosome is a key component of macrophages that is responsible for destroying bacteria. This particular variant caused a deficiency in an enzyme known as cathepsin, which acts within the lysosome like scissors to “chop up” bacteria; however, this would not necessarily explain why the macrophages could not destroy the bacteria, as many additional enzymes could take cathepsin’s place.
“The zebrafish-forward genetic screen was critical to identifying the connection between macrophage lysosomal trafficking defects and TB,” Moens said.
The key, the researchers found, lay in a second property of the macrophage: housekeeping. As well as destroying bacteria, the macrophage also recycles unwanted material from within the body for reuse, and these lysosomal-deficiency disorders were preventing this essential operation.
Ramakrishnan explains: “Macrophages act a bit like vacuum cleaners, hoovering up debris and unwanted material within the body, including the billions of cells that die each day as part of natural turnover. But the defective macrophages are unable to recycle this debris and get clogged up, growing bigger and fatter and less able to move around and clear up other material.
“This can become a problem in TB because once the TB granuloma forms, the host’s best bet is to send in more macrophages at a slow steady pace to help the already infected macrophages.”
“When these distended macrophages can’t move into the TB granuloma,” added co-author Dr. Steven Levitte from UW, “the infected macrophages that are already in there burst, leaving a ‘soup’ in which the bacteria can grow and spread further, making the infection worse.”
The researchers looked at whether the effect seen in the lysosomal-deficiency disorders, where the clogged-up macrophage could no longer perform its work, would also be observed if the lysosome became clogged with non-biological material. By “infecting” the zebrafish with microscopic plastic beads, they were able to replicate this effect.
This discovery then led the team to see whether the same phenomenon occurred in humans. They found that the macrophages of smokers were similarly clogged up with smoke particles, helping explain why people exposed to smoke were at a greater risk of TB infection.
This finding helps explain why exposure to cigarette smoke or smoke from burning wood or coal is a major risk factor for developing TB. Stopping smoking, in turn, reduces the risk by allowing damaged microphages to die and be replaced by healthy cells.
The research was supported by the National Institutes of Health, the Wellcome Trust, the National Institute of Health Research Cambridge Biomedical Research Centre, the Health Research Board of Ireland and The Royal City of Dublin Hospital Trust.
Based on a University of Cambridge news release