December 16, 2008 — The first trial to show an overall survival advantage for radiotherapy in the primary treatment of prostate cancer has been published online December 16 in the Lancet. It also shows that for older men with locally advanced prostate cancer, adding radiation to androgen-deprivation therapy halves their risk of dying from the disease.
The 10-year prostate-cancer-specific mortality in men treated with endocrine therapy alone was 11.9%, compared with 23.9% in men who received only endocrine therapy. The relative risk for cancer-specific death was 0.44 (P < .0001).
There was also a significant reduction in 10-year overall mortality: 29.6% in the combined-therapy group vs 39.4% in the endocrine-therapy group. The relative risk for overall death was 0.68 (P = .004).
These results come from the Scandinavian Prostate Cancer Group Study 7 (SPCG-7), also known as the Swedish Association for Urological Oncology-3 (SFUO-3) trial. The authors, headed by Anders Widmark, MD, professor of radiation oncology at Umeå University, in Sweden, say that endocrine therapy plus radiation should be the new standard of care for such patients.
The authors of an accompanying editorial agree. "Long-term hormonal therapy has long been regarded as the mainstay of treatment for men with locally advanced prostate cancer," write editorialists Chris Parker, MD, and Alex Tan, MD, from the Institute of Cancer Research, in Surrey, United Kingdom. "These results should change clinical practice," they say, so that long-term hormonal therapy plus radical radiotherapy becomes the new standard.
These results were first presented a few months ago at the American Society for Therapeutic Radiology and Oncology (ASTRO), as reported by Medscape Oncology. At the time, incoming president of ASTRO, Anthony Zietman, MD, from Massachusetts General Hospital, in Boston, predicted that these results would change clinical practice.
"At present, there is a bit of a fatalistic attitude toward locally advanced prostate cancer, as it is generally considered to have already quietly spread elsewhere," he commented. This attitude may be more common in Europe, but it is also prevalent in the United States. As a result, older men at this stage of the disease are often offered only hormonal therapy, he explained.
The thinking is that the cat is already out of the bag.
"The thinking is that the cat is already out of the bag," Dr. Zietman commented, but "the results from this trial prove that this is not the case."
Significant Superiority of Combination
The published results are exactly the same as those presented at the meeting, but now there are more details, plus an independent commentary.
The trial was conducted in 875 men at 47 centers in Norway, Sweden, and Denmark. The results are reported for a median follow-up of 7.6 years (range, 0.2 - 11.9 years). From these figures, the authors calculated cumulative incidence at 7 and 10 years.
Scandinavian Prostate Cancer Group Study 7: Comparison of Treatments
| Cause of death | Radiotherapy plus endocrine treatment | Endocrine treatment alone |
| Prostate cancer | 37/436 (8.5%) | 79/439 (18.0%) |
| Something other than cancer | 56/436 (12.8%) | 52/439 (11.8%) |
"The present study indicates a significant superiority of endocrine plus radiotherapy treatment compared with endocrine alone in patients with locally advanced prostate cancer," the authors conclude.
This is a "pivotal trial," the editorialists comment, adding that it is "the first to show an overall survival advantage for radiotherapy in the primary treatment of cancer."
More Adverse Effects With Combination
Patients who received the combination therapy had more adverse effects that were judged by physicians to be moderate or severe. At 5-year follow-up, significantly more patients who received both radiation and endocrine therapy had urinary incontinence, urgency, urethral stricture, and erectile dysfunction. In addition, patient-reported diarrhea was significantly more frequent at 4 years.
"Patient acceptability was high (over 85%) and the side effects of adding radiotherapy are acceptable in comparison to the survival gain achieved," Dr. Widmark and colleagues comment.
Hormone Therapy Used Was Unconventional
All patients were given endocrine treatment and total androgen blockade with the lutenizing hormone-releasing hormone agonist leuprorelin (Procren depot, Abbott) and the oral anti-androgen flutamide (Eulexin, Schering-Plough) for 3 months. After that, that flutamide was continued until progression or death. If anti-androgen adverse effects became evident, flutamide was stopped and then restarted at a lower dose; if this failed, patients were switched to bicalutamide.
"The hormonal therapy used in the trial is unconventional," the editorialists state, and there are no published data to show the efficacy of the regimen that was used, they point out. Standard hormonal therapy is with androgen deprivation alone, and bicalutamide monotherapy is generally regarded as an acceptable alternative.
"However, the regimen was the same in both groups of the trial, and one would envisage that the benefits seen for radiotherapy [in this trial] would also apply to patients on standard hormonal treatment," they add. This very issue is being examined in an ongoing trial, the National Cancer Institute of Canada Clinical Trials Group PR3 and Medical Research Council PR07 (NCIC PR3/MRC PRO7), and these results "will now be eagerly awaited."
Results Could Be Even Better With Modern Radiotherapy
According to the study authors, half of the patients were randomized to also receive radiation, administered by a standard 3-dimensional radiotherapy technique. A prescribed central dose (of 50 Gy) was applied to the prostate and seminal vesicles, and a sequential boost of at least 20 Gy was added to the prostate.
The trial was not blinded, which raises the possibility of bias, the editorialists comment. "It is at least plausible, though unlikely, that the investigators underplayed the toxic effects for patients in the radiotherapy group, treated them more intensively on relapse, and were less likely to attribute their deaths to prostate cancer."
"Although the physician-reported data for toxic effects must be viewed with caution," they continue, "there is no disguising the fact that radiotherapy led to improved overall survival, which is not just an important observation, but also an objective one."
"Indeed, it is possible that the trial could underestimate the true benefit of radiotherapy," the editorialists comment. The radiotherapy technique used was routine when the study was designed, they note, but "contemporary treatment with better methods of normal tissue avoidance, and thus higher doses to the prostate and pelvic lymph nodes, might be still more effective.
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