Radiation dose escalation fails to improve OS in PCa

Dose escalation does not improve overall survival among patients with intermediate-risk prostate cancer, according to a new study looking at outcomes from 104 radiation therapy oncology groups in the U.S.

“We had hoped that by better controlling the primary tumor it would translate into an improvement in overall survival. But it did not,” according to study author Jeff M. Michalski, MD, MBA, of Washington University School of Medicine in St. Louis.

However, there were significant improvements among those studied on the higher radiation dose in terms of biochemical failure and distant metastases. And while high radiation doses caused more late toxic effects, patients in the standard dose arm of the study had lower rates of salvage therapy.

For the research, which was published in JAMA Oncology (March 15, 2018 [Epub ahead of print]), the authors studied about 1,500 patients with intermediate-risk prostate cancer, who received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy. Among those, 748 men received the standard 70.2 Gy in 39 fractions, while 751-the investigational group-received increasing doses up to 79.2 Gy in 44 fractions.

Read: MRI-targeted Bx found superior to standard approach

Three quarters of the men in the standard group survived after a median 8.4-year follow-up, versus 76% in the investigational group. At 8 years, rates of mortality from prostate cancer were not statistically different, at 4% in the standard radiation dose group, compared to 2% among those receiving the escalated dose.

Secondary outcomes included the 8-year cumulative rate of distant metastases, which was 4% in the 79.2-Gy arm, versus 6% in the 70.2-Gy group. Biochemical failure at 8 years was 20% with 79.2 Gy and 35% with 70.2 Gy-a statistically significant difference. The rate of salvage therapy was significantly reduced with the use of the higher dose of radiation. But high doses caused more late toxic effects.

Today, urologists and other providers measure the success of radiation treatment by PSA outcome, according to Dr. Michalski.

In two biochemical control measures used in this study-the Phoenix definition, a PSA >nadir+2ng/mL and the older American Society for Radiation Oncology definition, which is three consecutive rises in PSA after nadir-Dr. Michalski and colleagues found a rather large improvement in outcome with dose escalation.

“While biochemical control doesn’t mean differences in survival, it does mean a lot to the emotional well-being of the patient to know that their PSA is maintaining a very low level. If the PSA rises, oftentimes, patients will undergo additional investigations or additional therapies that have considerable side effects and toxicity,” he said.

Next: Higher dose significantly lowers risk of distant metastases

Another important endpoint for patients is the rate of distant metastases, where the higher dose of radiation significantly lowered that risk.

“I think patients would prefer not to have metastatic disease and prefer not to face a question of additional or salvage therapy,” Dr. Michalski said. “The important lesson, here, is that if you’re facing a patient in which your radiation planning cannot obtain the appropriate sparing of the organs at risk-the bladder and rectum, in particular-you should probably back off on your prescription because… first, do no harm. And if you can’t deliver a dose of radiation that will improve biochemical and clinical outcomes, don’t put the patient at risk of injury because you’re not going to improve survival by doing so.”

This and related studies are adding to the knowledge about how to keep radiation safe, according to Dr. Michalski.

“In fact, a few years ago, we looked at the high-dose arm of this study, and we looked at patients who were treated with IMRT, versus 3D conformal radiation therapy. The patients with IMRT were more likely to have lower doses of radiation to their rectum and bladder and better tolerance to the treatment,” he said. “So, IMRT can reduce the dose of radiation to the rectum. Providers should follow those guidelines in terms of what doses are safe to the rectum and bladder, and if they can’t meet those guidelines, they need to back off on the prescription.”

Also see: Multivitamin use may reduce prostate Ca recurrence

Researchers have also found that the addition of hormone therapy for men in the intermediate-risk category might improve outcomes and, in some cases, survival.

“So, as an alternative to dose escalation, you might consider 4 to 6 months of hormone therapy, along with lower dose radiation, because that would be more likely to lead to better cancer control and survival outcomes if you can’t achieve dose escalation safely,” Dr. Michalski said.

In recent years, there have been many changes in how physicians treat prostate cancer with radiation. One example, while this study used 44 treatments in patients with intermediate-risk prostate cancer, a recent study by Dr. Michalski and colleagues suggests it is safe to shorten the overall course of radiation for patients with low-risk and intermediate-risk prostate cancer.

“Now we can reduce that to 20, 25, or 28 treatments, depending on the dose per day. We’re seeing more hypofractionation,” he said. “But for the patients with the highest risk disease, where we still need to treat the lymph nodes and seminal vesicles, I think it’s probably safest to maintain the longer course of radiation.”

The increased knowledge about how to safely and effectively deliver radiation is allowing providers to tailor radiation prescriptions according to what is most appropriate for individual patients and their disease states, according to Dr. Michalski.

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