The final analysis of the Phase II PR3 MRC/PRO7 NCIC trial, reported at the ASCO Annual Meeting, confirms that adding radiotherapy to androgen-deprivation therapy (ADT)—with luteinizing hormone-releasing hormone agonists or bilateral orchiectomy—significantly reduces the risk of death in men with locally advanced prostate cancer.
The results(Abstract 4509), which were presented by Professor Malcolm Mason, MD, Director of the Institute of Cancer and Genetics at Cardiff University in the UK, demonstrate that there is a “sustained and substantial overall survival and disease-specific survival benefit,” he and his coauthors concluded.
Competing risk analysis showed that men on ADT alone had a significantly higher chance of dying of disease-related causes than those treated with ADT+RT—the 10-year, cumulative, disease-specific death rates were 15 percent with ADT+RT and 25 percent with ADT alone (p<0.0001).
The trial ran from 1995 to 2005 and randomized 1,205 patients to lifelong ADT only (602 patients) or ADT plus radiotherapy (603 patients). A total of 465 patients have died: 260 on ADT, 205 on ADT+RT.
Adding RT to ADT significantly reduced the risk of death: 199 patients died—134 on ADT alone and 65 on ADT+RT.
“In the interim analysis we showed that adding RT halved the risk of dying from locally advanced disease, and we have been able to sustain this benefit with a median follow-up of eight years,” said Professor Mason, a member of the Editorial Board of OT's UK Edition.
In fact, the results were so positive at the interim stage—reported at the 2010 ASCO Annual Meeting (Abstract CRA4504)—that he and his co-researchers recommended that the combination became standard treatment for locally advanced prostate cancer. However, uptake was slow.
“We need to turn the clock back to look at what the prevailing view was then,” he said in an interview after the meeting. “When this study was set up in the 1990s, there was a very different view to what we have today: the disease was treated with hormone therapy alone and people were very skeptical about the use of radiotherapy because of the toxicity involved.
When he presented the interim analysis of this study at the 2010 ASCO Annual Meeting, he added, there were already two other groups that had done similar work: One, by Widmark et al (Lancet 2009;373:301–308) and the other, a French study, also presented at ASCO 2010 (Motter et al:Abstract 4505, now available as a full report in European Urology2012;62:213–219).
“However, ours is the biggest study,” Mason said. “We have the longest follow-up, the most mature data, and the type of hormone therapy used chimes with the sort used in North America and most parts of Europe.”
The final analysis, he continued, underlines what came out at the interim—“and now we can be sure it is a sustained and substantial overall survival and disease-specific survival benefit. So it underlines what we set out to show—that if you have men with locally advanced disease who are fit enough to have RT, they really should be offered it and not treated with hormone therapy alone.”
He noted that adding radiation therapy to ADT did produce some gastrointestinal toxicity, with a small effect on health-related quality of life. But overall the final analysis did not show much difference in the side-effects profile between the two groups.
Mason cautioned that when he and his colleagues began the study in the 1990s the doses of radiotherapy used were lower than those used now—and of course the higher the dose of radiotherapy the greater the side-effects profile.
“But at least these side effects really don't justify an argument for saying don't use radiotherapy. Now we use higher doses, but, of course, planning and technology have advanced, so that the treatment is much more accurate than it was. And there is a wealth of data out there now on the side effects and safety of modern RT.
“The message really is that the survival benefits from adding RT substantially outweigh worries about side effects—although, of course, patients must be counselled about these.”
The study's Discussant, Eric J. Small, MD, Professor of Medicine and Urology and Co-Director of the Urologic Oncology Program at the University of California San Franciso, said the results showed clearly that the combined-modality therapy offers patients with locally advanced prostate cancer increased survival with “little in the way of toxicity.”
Furthermore, he said, “monotherapy with ADT, as a rule, should not be considered a standard of care for these patients if overall predicted survival is greater than three to five years,” the point at which the survival curves begin to diverge.
Several questions remain unanswered, though, he said: For example, “most of the patients in the trial were T3, T4 patients, and a relative minority were Gleason Score 8 or higher, whereas in the current environment, at least in the U.S., most high-risk patients have lower-stage and higher Gleason score disease. That shouldn't preclude the inclusion of these patients with this therapy, although many may be equally well suited for radical prostatectomy. Certainly these patients should not get androgen-deprivation therapy alone.”
Also remaining to be determined, he said, are the role of intensity-modulated radiation therapy or three-dimensional conformal radiotherapy, the duration of ADT, and the inclusion of novel androgen receptor targeted therapies. In addition, “the slight increase in secondary malignancies warrants further evaluation, but nevertheless, this is a critical study that should form the basis for the standard approach to these patients.”
Anthony Zietman: ‘Remarkable and Important Trial’
Asked for an opinion for this article, Anthony Zietman, MD, Professor of Radiation Oncology at Harvard Medical School and Massachusetts General Hospital, said, “I think this is a most remarkable and important trial. It shows that patients with locally advanced prostate cancer should not simply be abandoned to a palliative approach with hormonal therapy alone. They have a significant chance for cure with the combined therapy, and the low level of bowel side-effects, in my mind, is well worth it.
“Obviously,” he continued, “this approach will be tailored in real-world practice—perhaps maintaining the hormone therapy-alone approach for the very elderly but offering some new hope for those with a longer life expectancy.”