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Higher doses of targeted radiation better than expected for aggressive early prostate cancer, study suggest

ANN ARBOR, Mich. - Early-stage prostate cancer patients with the most aggressive form of the disease may benefit more from high doses of carefully delivered radiation than previous reports would suggest, a new multi-center study led by current and former University of Michigan Comprehensive Cancer Center researchers has found.

In fact, the study showed that X-rays delivered to the exact three-dimensional location of 180 high-risk tumors kept 79 percent of early-stage patients cancer free for at least five years -- a remarkable improvement over the usual 50-percent recurrence rate for those who have their prostates removed or have lower-dose radiation therapy.

The study, which shows a clear positive effect from higher doses, is published in the current issue of the International Journal of Radiation Oncology, Biology and Physics. It adds to years of U-M research into lower radiation doses for less-severe prostate cancer and other tumors.

The research involved only patients with rarer but more often deadly forms of prostate cancer. But its results suggest that higher doses of 3-D conformal radiation, as it is called, may help prostate cancer patients with less-dangerous types of the disease, says study senior author Howard Sandler, M.D., associate professor and associate chair of radiation oncology in the U-M Health System.

"This new evidence of an advantage from higher doses not only validates the use of this approach in this subgroup of high-risk patients, it also hints strongly that lower-grade tumors could be vulnerable to increased radiation delivered with careful planning," says Sandler.

Sandler and former U-M fellow John Fiveash, M.D., now at the University of Alabama-Birmingham, teamed with other researchers from the U-M the Fox Chase Cancer Center in Pennsylvania and the University of California, San Francisco to pool data for the study.

They looked back at how well patients with the highest-grade kinds of tumors did after treatment with radiation doses as much as ten percent more intense than conventional levels. As with all 3-D conformal radiation therapy, patients received the doses after high-resolution images of their individual tumors allowed doctors to plot the best angles for aiming the radiation beam at the tumor's exact outline, while skirting important normal tissue like the bladder and hip bones.

3-D conformal radiation therapy was pioneered clinically in the mid-1980s at the U-M and elsewhere under the leadership of radiation oncology researchers like Allen Lichter, M.D., now dean of the U-M Medical School. It combines recent advances in medical imaging, which allow 3-D images to be made of the body with high resolution, with sophisticated radiation equipment that can produce many thin beams of intense X-rays and aim them with pinpoint accuracy. It has few side effects.

Physicians can look at a virtual representation of a tumor with a "beam's eye view" that shows them the irregular cross-section shape of each patient's cancer and predicts exactly where each beam of radiation will pass through the body. Then, using planning software, careful patient positioning and specially designed shutters for the X-rays to pass through, they can generate a combination of beams from different angles that will intersect when they reach the tumor. "This delivers a combined dose of radiation powerful enough to kill cancer cells, even though the individual beams leave nearby normal tissue relatively unscathed," says Sandler.

The U-M has used 3-D conformal radiation therapy for more than a decade as standard radiation therapy. Now, studies such as this one aim to optimize its effectiveness by studying what happens when radiation dose to the tumor is carefully stepped up. Meanwhile, U-M researchers are developing the next generations of hardware and software to make radiation delivery even more precise and harmless to non-cancerous tissue than it already is.

The new study looked at the survival time and cancer-free time -- defined as the period in which patients' blood showed no increase in prostate-specific antigen, or PSA -- of patients whose cancer cells showed microscopic evidence of being especially aggressive.

Pathologists rate tumor biopsy samples from 1 to 10 on what is known as the Gleason scale, which ranks "normal" looking cells low and gives higher scores to more abnormal-looking ones which have the potential to grow out of control. All patients in the study had the highest Gleason ratings, from 8 to 10 -- ratings that appear relatively rarely among all prostate cancer patients but disproportionately among the 39,000 men who die from the disease each year.

In addition to Gleason score, which rates the tumor's growth potential, the study also looked at the stage of each patient's cancer at the time of radiation therapy. Stages, ranging from 1 to 4, rate how far the cancer has spread within, around and beyond the prostate.

Patients in the study received radiation almost daily for several weeks, resulting in doses that ranged from the currently conventional -- around 66-70 Gray, or Gy -- all the way up to 80 Gy. Even though the difference in dose sounds small, the increase in radiation effect upon the tumor is large.

Of the 180 patients, 61 percent had a Gleason score of 8, and 57 percent had stage 1 or 2 cancer. Their average age was 72, and follow-up time averaged three years but ranged up to 8 years. Some patients took hormone-reducing drugs as well, though no effect was seen.

In all, 62.5 percent stayed within PSA limits, showing no recurrence of their cancer, for five years, and 67.3 percent survived five years. But, Sandler says, "the most dramatic effect was seen in stage 1 or 2 patients with lower pre-treatment PSA levels who received the highest radiation doses -- suggesting that the therapy works best for those who catch their aggressive cancer early. By comparison, recent examinations of conventional radiation therapy and surgery have shown recurrence rates higher than originally thought."

 

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