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Prostate Cancer: Short-Term ADT Added to Radiation Reduces Biochemical Relapse, but Questions Remain about Toxicity

Goodwin, Peter

doi: 10.1097/01.COT.0000451733.88044.a5
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VIENNA—Adding six months of androgen-deprivation therapy (ADT) to radiation therapy for men with intermediate- or high-risk (T1b-cT2aN0M0) localized prostate cancer halved the rates of biochemical progression at five years in a Phase III randomized study reported here at the European Society for Radiotherapy and Oncology (ESTRO) Conference (Abstract OC-0522).

The study, which was supported by the European Organisation for Research and Treatment of Cancer, was conducted in 37 centers and 14 countries and included 819 men randomized to have six months of ADT (two injections of an LH-RH analogue and a total of one month of anti-androgens) added to their three-dimensional conformal radiotherapy (3D-CRT), delivered with or without intensity modulation at fractionated doses ranging from 70 to 78 Gy with pelvic node irradiation used at the discretion of each institution.

The lead investigator, Michel Bolla, MD, Professor of Radiation Oncology at Grenoble University Hospital, France, concluded that the findings imply that such short-term ADT needed to be added to conformal radiotherapy (whether intensity modulated or not, and regardless of the dose level) to obtain a significant decrease in risk of relapse: “These results show that in men with localized prostate cancer at risk of recurring and spreading, the addition of six months of hormonal treatment to radiotherapy improves the time these men survive without their disease progressing,” he reported in a news briefing.

Taking all radiation doses, 82.5 percent of patients treated with the combination survived five years without biochemical progression (assessed by PSA values that increased above the lowest level plus two nanograms per milliliter) compared with a relapse-free rate of 69.3 percent among those treated with radiation alone: an increase of 13.2 percent.

Five-year clinical progression-free survival was also significantly improved, by 7.9 percent, but the incidence of late genitourinary toxicity (mainly urinary) was up by almost six percent in patients on combination therapy versus 3.6% among those receiving radiation alone. And more patients randomized to the combination (27.0%) had severely impaired sexual function than those receiving radiation alone (19.4%).

Bolla said in an interview after the meeting that patients need to weigh the benefits of the treatment against the potential side effects—including heart disease and the metabolic syndrome: “Provided the patient is duly informed about the potential advantage and disadvantage of this medication, we have to prescribe this combination,” he said, adding that side effects could be well managed in a multidisciplinary environment with the help of family physicians, even for patients with diabetes or heart disease.

Asked for his opinion for this article, Tom Pickles, MB, MD, MRCP, FRCP, of the Division of Radiotherapy and Developmental Radiotherapeutics at the University of British Columbia, complimented the trial as “a real accomplishment” in being able to include so many patients.

He said he was disappointed, though, about the low efficacy of current and recent image-guided external-beam radiotherapy, acknowledging that the documented gain in biochemical progression-free survival (BPFS) would likely encourage clinicians and patients to consider short-term ADT as an option to treat intermediate-risk localized prostate cancer, although he remained unconvinced as yet that the case had been proven.

He questioned the value of using BPFS as a primary outcome for the study, which he described as “very useful” from the physician's point of view: “But from the patient's point of view it isn't really that important.” He said he regarded endpoints such as spread of the cancer—particularly metastases—or dying of cancer as more important for patients.

The use of external radiation in the form given in the trial is “inadequate,” Pickles said. Although adding hormone therapy was an improvement, it was not enough: “It's really not the solution. For me the most important hard endpoint presented was freedom from metastases.”

He said he thought the fact that six percent of patients receiving radiation alone had metastatic spread as compared with only two percent among those receiving the combined treatment might be considered a benefit, but that when balanced against the toxicity of ADT among the majority of men who derived no benefit from it, the combination was harder to recommend overall.

MICHEL BOLLA, MD

MICHEL BOLLA, MD

Pickles also said he was not convinced that quality-of-life issues were adequately addressed in the new study: “We know that every man who's put on ADT suffers in terms of some side effects, so to expose the majority to these side effects without benefit is a concern.”

He was also cautious about any potential reversal of the recent trend towards minimizing the use of ADT—“The emerging evidence is that it is harmful.”

However identifying patients who are potential net beneficiaries of short-term ADT could in the future possibly help a subset of patients receive a benefit.

Pickles said he preferred to look to other modalities such as brachytherapy, for which there has already been encouraging Phase II data, for supplementing the effect of external-beam radiotherapy: “There is good emerging evidence that by using brachytherapy as a boost to the external radiation you can get better control rates than are being seen in this study with hormone therapy,” he said.

Bolla said he agreed that there was room for improving radiotherapy, but he said he remained convinced that ADT could become a key player in the treatment of localized prostate cancer.

In a news release from the conference, ESTRO Immediate Past President Vincenzo Valentini, MD, a radiation oncologist at Policlinico Universitario A. Gemelli in Rome, described the results from the trial as important and practice-changing: “It is clear that six months of hormonal treatment in addition to radiotherapy improves the outcome for men with localized prostate cancer,” he said. “This option should now be considered for all these men with prostate cancer that is at risk of growing and spreading.”

© 2014 by Lippincott Williams & Wilkins, Inc.
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