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Prostate Cancer: Long-Term Anti-Androgens Added to Salvage Radiation Extend Survival

Carlson, Robert H.

doi: 10.1097/01.COT.0000475699.81589.17
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Prostate Cancer RTOG 9601 Still Relevant after All These Years

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SAN ANTONIO—Salvage radiotherapy plus 24 months of androgen blockage with bicalutamide, when compared with radiotherapy alone, extended long-term overall survival and reduced death from prostate cancer without adding significantly to radiation toxicity in the placebo-controlled Phase III NRG Oncology/RTOG 9601 trial. While trial planning began 20 years ago and the trial was activated in 1998, the findings are still relevant to patient care today.

That was the conclusion of the researchers and the Discussant here at the American Society for Radiation Oncology Annual Meeting, where the data were presented in the plenary session (Abstract LBA5).

The study's lead author, William U. Shipley, MD, Distinguished Professor of Radiation Oncology at Massachusetts General Hospital and Harvard Medical School, presented final outcomes from what he termed “this somewhat venerable salvage radiation trial.”

Shipley said that with the addition of peripheral androgen blockade during and after salvage radiotherapy:

  • Actuarial overall survival at 10 years was 82 percent for radiotherapy plus anti-androgen therapy versus 78 percent for radiotherapy plus placebo;
  • The prostate cancer-specific death rate was reduced to 2.3 versus 7.5 percent, respectively;
  • The risk of metastasis at 12 years was reduced to 14 percent versus 23 percent; and
  • Late grade 3 and 4 bladder and bowel side effects were similar in both groups.

Although 70 percent of the men receiving anti-androgen therapy group reported gynecomastia, so did 11 percent in the radiotherapy-plus-placebo group, which Shipley said he thought was “just a matter of older males getting a little chubbier.”

The trial, treating 761 patients in the U.S. and Canada between 1998 and 2003, was supported by the National Cancer Institute and AstraZeneca, the maker of bicalutamide.

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Potential Limitations over Time

Patients in RTOG 9601 had undergone radical prostatectomy for tumors classified as T2pN0 with a positive surgical margin or T3pN0, and had or had developed elevated prostate-specific antigen (PSA) levels from 0.2 to 4.0 ng/mL.

The patients were randomly assigned to receive 64.6 Gy of radiotherapy in 36 fractions of 1.8 Gy plus 24 months of anti-androgen therapy of 150 mg of daily bicalutamide during and after radiotherapy (384 patients), or to radiotherapy and placebo (377 patients).

Shipley explained that statistically significant overall survival data in a prostate cancer trial necessarily takes more than a decade to acquire, and he acknowledged that this could limit the trial's relevance to today's practice decisions.

“The radiation doses and fields today may or may not be better than the ones we used in the 1990s; the surgical approach has been modified; we don't get pathologic evaluation of the lymph nodes done quite so frequently; anti-androgen therapy today is used much less frequently and we use androgen-deprivation therapy more often; and we are now treating salvage patients much earlier and with much lower-entry PSA values. All of this has to be taken into account.”

Shipley said further statistical analyses are underway, which may identify subgroups of prostate cancer patients who will not benefit from hormone therapy added to salvage radiotherapy, and others for whom it may be especially beneficial.

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Filling a Knowledge Gap

The Discussant for the study, Alan Pollack, MD, PhD, Professor and Chair of the Department of Radiation Oncology at the Sylvester Comprehensive Cancer Center at the University of Miami, said: “We have a lot of data on treating primary prostate cancer with radiotherapy and androgen deprivation, but there is a knowledge gap for men treated for salvage therapy for a rising PSA. RTOG 9601 attempts to sort that out by directly addressing this issue.”

Pollack said suboptimal results for salvage radiotherapy alone were illustrated in a pooled multi-institutional study, on which he was senior author, showing a 10-year freedom of biochemical failure rate of only 20 percent (Stephenson et al: JCO 2007;25:2035-2041). “And more than 50 percent of those patients failed within six years—even patients with very favorable features such as a low pre-treatment PSA.”

He gave credit to the RTOG 9601 investigators for reaching their target accrual so that the overall-survival endpoint could be statistically significant.

Pollack said the follow-up took place over a period of time when overall survival in men with prostate cancer was improving, according to a recent study (Edwards et al: Cancer 2014;120:1290-1314): “That could have affected the power of this study, but a survival advantage was still seen. What is striking, in terms of freedom from progression including biochemical failure, is that there is quite a difference between the curves when you add the two years of anti-androgen therapy.”

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Practical Application

“How do we practically apply this level 1 evidence—determining which salvage patients require androgen-deprivation therapy?” Pollack continued.

Probably all but the very best, he said—that is, all but patients with pre-radiotherapy PSA levels of less than 0.5 ng/mL, lower-grade disease, and no seminal vesicle involvement. “And which salvage patients would definitely benefit from long-term androgen-deprivation therapy versus short-term? Probably those with seminal vesicle involvement, a pre-radiotherapy PSA of greater than 1.0 ng/mL, pathologic T3b or greater, or PSA doubling time of six months or less.”

Pollack said the results of the GETUG-AFU 16 trial (Carrie et al: ASCO 2015 Abstract 5006) should also be considered, showing the impact of short-term androgen deprivation added to radiotherapy.

The study is relevant to patients today, he said: “Radiotherapy techniques have changed since the study was initiated, with slightly higher prostate-bed doses on average today, but the impact of the changes has more likely been on toxicity rather than on tumor control. And we can assume that tumor control is probably going to be similar, although we use higher doses today.”

In addition, intensity-modulated radiation therapy and image guidance are more likely to be used today.

But the characteristics of the patients in the study are approximately the same as today, with a median PSA level of 0.6 ng/mL, Pollack said. And the benefit of standard androgen-deprivation therapy today, compared with that of bicalutamide at 150 mg, is more likely to be similar or even better in terms of survival.

“The results demonstrate the importance of adding androgen-deprivation therapy to prostate-bed radiotherapy for patients receiving salvage therapy, showing a survival advantage and results that parallel those seen in men treated with androgen deprivation and radiation as primary treatment,” he concluded.

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Potential to Change Practice

Another speaker at the meeting, Howard M. Sandler, MD, Professor and Chair of the Department of Radiation Oncology at Cedars Sinai Medical Center, who presented his own study showing that a shorter radiation therapy schedule can be as effective as a conventional one for men with low-risk prostate cancer, also commented on RTOG 9601: “This study will change the practice standard even though it was designed in about 1996.”

And ASTRO President David C. Beyer, MD, who was moderator of a news conference on “Refining Treatments for Prostate Cancer” that included both studies, said he thought RTOG 9601 has the potential to change practice: “Clearly from this data, androgen-deprivation therapy is the standard of care for some patients. It's not currently the standard of care to deliver hormonal therapy along with salvage radiation for prostate cancer patients, but seeing not only some PSA benefit but also overall survival benefit from anti-androgen therapy has got to wake people up.

“I don't currently offer hormonal therapy for my patients who are getting salvage external-beam radiation—but I will tomorrow.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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