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Higher radiation doses not improving survival in prostate cancer patients

A study shows that higher doses of radiation do not improve survival for many patients with prostate cancer, compared with the standard radiation treatment. The analysis, which included 104 radiation therapy oncology groups across North America, was led by researchers at Washington University School of Medicine in St Louis.

Past studies have shown that gradually escalating the radiation dose resulted in improved cancer control, such as slower tumour growth and lower levels of prostate-specific antigen (PSA), an indicator of cancer growth. The study is the first that is large enough to examine whether these improved measurements translate into longer survival for patients.

"Our goal is to improve survival, but we didn't see that despite advances in modern radiotherapy," said first author Dr Jeff M Michalski, the Carlos A Perez distinguished professor of radiation oncology. "But we did see significantly lower rates of recurrence, tumour growth and metastatic disease – tumours that spread – in the group that received the higher radiation dose. Still, that didn't translate into better survival. The patients in the trial did better than we anticipated, and part of that may have been because of improvements in metastatic cancer therapy over the 10 years of the trial."

The study included about 1,500 patients with intermediate-risk prostate cancer, the risk category in which most patients fall. To be classified in this risk category, patients generally have PSA scores of 10-20 ng/ml and a Gleason score of seven, the latter of which is a measure of tumour aggressiveness. Both treatment groups received external beam radiation. The standard group received a radiation dose of 70.2 grey delivered over 39 treatment visits. The investigational group received increasing doses up to 79.2 grey delivered over 44 visits. (A grey is the standard measure of radiation a material has absorbed.)

Of the 748 men receiving standard treatment, 75% were still alive after eight years of follow-up. Of the 751 men receiving the dose-escalation treatment, 76% were alive at the eight-year mark – a difference that is not statistically significant. These overall survival rates include deaths for any cause, not just those due to prostate cancer. Over the course of the study, 51 patients died of prostate cancer, which is 3.4% of all patients enrolled.

At the eight-year mark, the death rate due to prostate cancer for patients receiving standard treatment was 4% compared with 2% for patients receiving the escalating dose. These rates also were not statistically different.

While there was no difference in overall survival numbers, Michalski pointed out some differences in side effects and in whether further treatment was needed later. Such differences could help doctors and patients in deciding the best treatment course.

Patients in the standard dose group were more likely to undergo further therapies to control tumours that had grown larger or that had spread to another site in the body. But patients in the escalating dose group experienced more side effects – such as urinary irritation or rectal bleeding – sometimes years after treatment.

During the 10 years it took to enrol enough patients in the trial, Michalski said, at least six new therapies were approved for recurrent or metastatic prostate cancer, and these therapies have been shown to improve survival. It is possible the patients in the standard treatment arm – who were shown to need more follow-up therapies – would not have done as well as the group receiving the escalating dose had these new therapies not become available.

"If there is a difference between standard and escalating doses, it's hard to show it when the patients who later develop recurrent cancer can have their lives extended through the use of additional therapies," said Michalski, who treats patients at Siteman Cancer Centre at Washington University School of Medicine and Barnes-Jewish Hospital. "Of course, these additional therapies have their own side effects, as does the higher initial dose of radiation therapy. In addition, the selective use of androgen withdrawal therapy has been shown to improve survival in men treated with radiation therapy. This treatment can be combined with either standard or higher dose radiation therapy."

"If we can safely deliver the higher dose of radiation, my opinion is to do that," Michalski added. "It does show lower risk of recurrence, which results in better quality of life. But if we can't achieve those 'safe' radiation dose goals, we shouldn't put the patient at risk of serious side effects down the line by giving the higher dose. If we can't spare the rectum or the bladder well enough, for example, we should probably back off the radiation dose. It's important to develop treatment plans for each patient on a case-by-case basis."

Importance: Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences.
Objective: To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer.
Design, Setting, and Participants: The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions.
Main Outcomes and Measures: Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively.
Results: With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA <10 ng/mL, 84% Gleason score of 7, 57% T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (hazard ratio [HR], 1.00; 95% CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy and 47% and 35% with 70.2 Gy, respectively (both P < .001; ASTRO: HR, 0.59; 95% CI, 0.50-0.70; Phoenix: HR, 0.54; 95% CI, 0.44-0.65). The high-dose arm had a lower rate of salvage therapy use. The 5-year rates of late grade 2 or greater gastrointestinal and/or genitourinary toxic effects were 21% and 12% with 79.2 Gy and 15% and 7% with 70.2 Gy (P = .006 [HR, 1.39; 95% CI, 1.10-1.77] and P = .003 [HR, 1.59; 95% CI, 1.17-2.16], respectively).
Conclusions and Relevance: Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy.

Michalski JM, Moughan J, Purdy J, Bosch W, Bruner DW, Bahary JP, Lau H, Duclos M, Parliament M, Morton G, Hamstra D, Seider M, Lock MI, Patel M, Gay H, Vigneault E, Winter K, Sandler H

[link url=""]Washington University School of Medicine in St Louis material[/link]
[link url=""]JAMA Oncology abstract[/link]

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