Finding a Benefit Inside a Risk

800px-paracetamol_acetaminophen_500_mg_pillsIn a perfect world, patients would only have one serious condition at a time that could be treated in isolation. But that’s not the case: when a doctor is considering treatment for one disease, they must take into account the other illnesses and treatments ongoing in a patient. Even relatively innocent and common drugs, such as the anticoagulants given to prevent blood clotting in people with certain heart conditions, can cause complications during medical procedures due to the risk of increased bleeding. But alongside the risks of those drugs, occasionally there’s an unexpected benefit that falls into the lap of researchers and clinicians.

Kevin Choe and Stanley Liauw set out to study this kind of drug interloper, testing whether prostate cancer patients on anticoagulants such as Coumadin or aspirin respond differently to radiation therapy. The primary aim of their study was to assess how strong anticoagulants such as warfarin or clopidogrel added to the risk of a common side effect experienced after radiation therapy. But the two also uncovered a useful secondary effect in their retrospective study of over 500 patients – a potential benefit of anticoagulants upon long-term outcomes after radiation therapy.

“This is the nature of research; sometimes, the less expected finding is the one that might have more potential interest,” said Liauw, assistant professor of radiation and cellular oncology.

More than 180,000 cases of prostate cancer are diagnosed each year, and the disease is more prevalent in elderly male populations. That same age group also is more likely to have cardiovascular problems that necessitate chronic treatment with an anticoagulant drug to prevent heart attacks and stroke. But while slowing the blood’s natural clotting ability is a good thing for heart disease patients on a normal day, it’s a profound negative during surgery. Even in radiation therapy for prostate cancer, bleeding rarely occurs due to damage to the rectal wall, which leads radiologists to use lower doses on patients taking anticoagulants.

To better define that additional risk, Choe, a fifth-year resident in the radiation oncology program, Ashesh Jani, and Liauw began a retrospective study of patients who had received radiation treatment at the University of Chicago Medical Center. The researchers looked at the records of nearly 600 patients who had already received their treatment and compared those patients who were taking warfarin or clopidogrel to those who were not. The comparison confirmed that there was indeed an increased risk of the side effect – 15.5 percent of patients on anticoagulants reported severe bleeding compared to only 3.6 percent of controls. As a result, the authors suggested that clinicians should use caution when increasing the radiation dose in patients on anticoagulants who are unable to stop treatment due to their other illnesses.

But the project didn’t end on that down note.

Based upon chatter and preliminary evidence in the cancer research community that anticoagulants may have a positive effect on cancer outcomes, Choe and colleagues did another retrospective analysis on the same group of patients, this time looking for a benefit of the drug. The news was good on at least two measures: biochemical control and metastasis. Patients on warfarin, clopidogrel or aspirin had a lower chance of cancer recurrence 4 years after treatment, as measured by a rise in PSA levels – a commonly-used chemical marker of treatment success. Anticoagulant use also correlated with significantly lower risk of the prostate tumor metastasizing to other sites in the body, with only a 1 percent rate in the drug group compared to 5 percent in the controls.

Those are both encouraging results to clinicians who treat prostate cancer, even if it remains unknown exactly how this anticoagulant effect occurs.

“Although we see this difference, we don’t really know why there’s a difference,” Choe said. “Are the drugs helping radiation become more potent? Or is it just innate to the tumors that whether you get surgery or radiation the benefit is going to be there? We don’t know.”

Those answers may lie in a larger retrospective study that Choe is already working on, using the CAPSURE database of prostate cancer patients from more than 20 clinical sites. Though that study will still have the caveats inherent in a retrospective analysis, such as the inability to randomize subjects and control for the type or dose of drug, it could yield further promising data that might inspire a more rigorous trial.

“The Catch-22 is that in order to generate hypotheses you need to start with studies like this one,” Liauw said. “There have been trials that study the effect of anti-coagulants on cancer outcomes, but very few of them. What’s warranted as the next step is not necessarily a clinical trial as an offshoot of this study but further retrospective interrogation and multi-institutional collaboration.”

Until those studies can be done, both Choe and Liauw said it was too early to weigh the risks and benefits and recommend a prostate cancer patient go on – or off – anticoagulants before radiation therapy. Further research may also reveal that some anticoagulant drugs are better than others in maximizing benefits without significantly elevating the side effects. A mild, over-the-counter anticoagulant, such as aspirin, may give a more positive balance to a patient than the prescription anticoagulants warfarin and clopidogrel, they said.

“That’s certainly a future project, to identify a drug that is not very toxic but at the same time offers the potential benefit, and I think something like aspirin would be a good candidate for that,” Choe said.

If aspirin were to show promise as a helpful force in recovery from prostate cancer, it’d be a cheap, simple supplement to radiation therapy. It would also be a benefit that might not have been discovered, if it wasn’t for its risk.

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Choe, K., Correa, D., Jani, A., & Liauw, S. (2010). The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy Cancer DOI: 10.1002/cncr.24890

Choe, K., Jani, A., & Liauw, S. (2010). External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity? International Journal of Radiation OncologyBiologyPhysics, 76 (3), 755-760 DOI: 10.1016/j.ijrobp.2009.02.026

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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