Friday, December 8, 2017

Exercise may make radiation more successful by overcoming hypoxia

Radiation therapy does not often fail in prostate cancer patients who are not already metastatic. Many had thought that most radiation failures are attributable to undetected micrometastases. However, two recent studies (see this link and this one) showed that about half of all failures of IMRT as primary therapy were due to failure to kill all the cancer within the prostate. One of the reasons that radiation may not destroy all the cancer is due to a condition called hypoxia.

Hypoxia refers to tissues that are not well oxygenated. Most solid tumors are hypoxic to some degree. The tumor tissue is denser than benign tissue, and although the tumor does generate its own blood supply, the blood vessels are leaky and haphazard. Cancer can often thrive in an hypoxic environment that would atrophy healthy tissue.

Good tissue oxygenation is essential for radiation to work. X-rays cause a chemical reaction with water and oxygen to generate what is called "reactive oxygen species (ROS)." The most important ROS is a molecule called a hydroxyl radical. The hydroxyl radical (a free radical) is powerful enough to tear apart DNA in a reaction called a "double strand break." This is where the magic of radiation happens. Healthy cells can repair double strand breaks or commit suicide (apoptosis) if they can't. Cancer cells lack the ability to repair double strand breaks. Then, when they eventually try to replicate (and that may be delayed for years), they fail to do so and die trying. So radiation irreversibly kills cancer cells but leaves most benign cells intact. But under hypoxic conditions not enough hydroxyl radicals are formed, and some of the cancer is left alive.

(Incidentally, it should be obvious from this that supplements that are marketed as antioxidants or free-radical absorbers (e.g., Vitamin E, Vitamin C, glutathione, alpha-lipoic acid, etc.), which are of questionable value at any time, should be especially avoided during radiation therapy.)

The most common solutions to overcome hypoxia are to increase the radiation dose and to use some fractionation. Increasing the dose blasts through the tumor like a steam blaster cleaning debris. Fractionation - smaller, multiple doses - kills the outer, oxygenated layer of the tumor. Then, as the outer layer falls away and the next layer gets a fresh blood supply, the next fraction kills that layer. It's like peeling away the layers of an onion. Prostate cancer is particularly vulnerable to a more intense radiation dose, which is why radiation techniques that increase dose per fraction (i.e., SBRT, HDR brachytherapy, and hypofractionated IMRT) are so effective. But at least some fractionation seems to be important too. Attempts to use just one fraction of HDR brachytherapy seem to have higher-than-expected failure rates (see this link).

Good tissue oxygenation seems to play a role in keeping healthy cells healthy following radiation. Kapur et al. in one small study found that moderate aerobic exercise throughout the radiation treatments reduced the incidence of acute rectal side effects. We recently saw that exercise reduces radiation-induced fatigue (see this link). Hyperbaric oxygen therapy has been used to reverse radiation-induced cystitis and proctitis (see this link) and hematuria, although one randomized controlled trial found it did not improve bowel inflammation or rectal bleeding.

So far, the evidence that exercise reduces tumor hypoxia has been limited to a study in rats (see this link). In the first study in humans that I'm aware of, a group at the University Hospital of North Norway are conducting a small clinical trial among 32 men who plan to have a prostatectomy. Half will undergo 4-5 weeks of moderate to intense supervised aerobic exercise. Half will not be told to exercise. They hypothesize that the aerobic exercise will increase the vascularity of the prostate tumors and thereby cause a sustained reduction in hypoxia. Before prostatectomy, they will all be injected with pimonidazole, a non-toxic drug that has particular affinity for hypoxic tissue. In post-prostatectomy pathology, it will be detected in prostate tissue using a specific antibody. They will also look at blood flow in the tumor prior to prostatectomy using MRI.

While this trial may prove that exercise reduces prostate cancer tumor hypoxia, it will remain for a future clinical trial to prove that radiation oncological and toxicity outcomes are improved by it. That will take several years, if it ever gets studied.

Meanwhile, this intervention is harmless for most patients (with doctor's permission, of course), and may improve the results of their prostate radiation treatment. While it may be ideal to undertake a 4-5 week supervised aerobic exercise program to permanently increase tumor vasculature or undergo hyperbaric oxygen therapy, as little as 15 minutes on a treadmill or an exercise bike within an hour of radiation treatment may be enough to temporarily increase tumor oxygenation.

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