NEOADJUVANT ANDROGEN DEPRIVATION THERAPY BEFORERADIOTHERAPY HALVES PROSTATE CANCER MORTALITY

New long-term results confirm the finding that neoadjuvant androgen-deprivation therapy (ADT), combined with radiotherapy, can significantly boost survival in men with locally advanced prostate cancer.
The updated results of the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial are published online March 25 in the Lancet Oncology.
They show that a large proportion of patients with locally advanced disease can be successfully treated with as little as 6 months of neoadjuvant ADT and a relatively low dose of radiation.
The authors note that at 10 years, neoadjuvant ADT cut the prostate-cancer-specific mortality rate in half, compared with radiation treatment alone (11% vs 22%).
All-cause mortality was also reduced, by about a third, among patients who received both therapies (29% vs 43%).
These results confirm the use of neoadjuvant ADT in this population of prostate cancer patients, explained lead author James W. Denham, MD, director of the Prostate Cancer Trials Group at the University of Newcastle, New South Wales, Australia. "It also gives evidence that the treatment needs to be at least 6 months to have an effect on mortality."
"For men with intermediate-risk cancers, RTOG [Radiation Therapy Oncology Group] 9408 has shown that 4 months of neoadjuvant ADT can improve survival," he told Medscape Medical News.
Earlier Results Confirmed
Dr. Denham and colleagues previously reported 5-year results from this study. They suggested that 6 months of neoadjuvant ADT improved prostate-cancer-specific survival by reducing metastases (Lancet Oncol. 2005;6:841-850). At 10 years, they now find that, compared with radiotherapy alone, the addition of ADT improves event-free survival, decreases the cumulative incidence of prostate-specific antigen (PSA) progression, and decreases distant progression and all-cause and disease-specific mortality.
In this prostate cancer population, neoadjuvant ADT for at least 6 months is the already the standard of care in Australia and New Zealand and a number of centers in other parts of the world, explained Dr. Denham.
He also noted that although a longer duration of ADT after radiation might increase survival slightly, which has been seen in some trials from the RTOG and European Organization for Research and Treatment of Cancer, it comes at a cost — both financially and in terms of toxicity. "A point we make in the article is that the informed treatment-consent process is getting much more rigorous in many countries, and it is getting more difficult to 'persuade' men that the inconvenience and potential prolonged ill effects of long-term ADT are worth the possible additional gains," he said.
"Six months of neoadjuvant ADT and radiation is a very reasonable choice, particularly for men with coexisting medical problems that could be exacerbated by long-term ADT," Dr. Denham added.
Clear Messages for Clinical Practice
In an accompanying editorial, Chris Parker, MD, consultant clinical oncologist from the Royal Marsden Hospital, Sutton, United Kingdom, agrees that these findings strengthen the evidence and send "2 clear messages for current clinical practice."
First off, he writes, is that it offers confirmation that neoadjuvant ADT "significantly reduces mortality after radiotherapy for high-risk prostate cancer, and is a standard of care."
The second point is that it helps to" resolve the uncertainty" regarding the duration of this therapy, and strongly suggests that the duration should be at least 6 months, he notes.
Six Months Superior to 3 Months
The TROG 96.01 study compared radiotherapy alone with 3 or 6 months of neoadjuvant ADT, which was given before and during radiation therapy. In their paper, the authors report, from the 10-year data, the benefits derived from 3 months and 6 months of neoadjuvant ADT.
Their analysis involved 802 men with stage T2b, T2c, T3, and T4 N0M0 prostate cancers. They were randomly assigned to receive radiotherapy alone (n = 270), 3 months of neoadjuvant ADT plus radiotherapy (n = 265), or 6 months of neoadjuvant ADT plus radiotherapy (n = 267).
At 10 years, prostate-cancer-specific mortality was 22% for radiotherapy alone, 18.9% for 3 months of neoadjuvant therapy (hazard ratio [HR], 0.86; P = .398), and 11.4% for 6 months of neoadjuvant ADT (HR, 0.49; P = .0008).
For all-cause mortality at 10 years, the findings were similar: 42.5% for radiotherapy alone, 36.7% for 3 months of neoadjuvant ADT (HR, 0.84; P = .18), and 29.2% for 6 months of neoadjuvant ADT (HR, 0.63; P = .0008).
Conversely, the cumulative incidence of deaths at 10 years not related to prostate cancer were similar in all treatment groups: 20.4% for radiotherapy alone, 17.7% for 3 months of neoadjuvant ADT, and 17.8% for 6 months of neoadjuvant ADT (P > .40 for all paired comparisons).
During the course of the study, 16,562 PSA levels were obtained from the 802 men; the median number of PSA levels per patient was 21 (range, 1 to 43).
Progression of PSA was observed in 508 men. At 10 years, the cumulative incidence of PSA progression was 73.8% for radiotherapy alone, 60.4% for 3 months of neoadjuvant ADT (HR, 0.72; P = .003), and 52.3% for 6 months of neoadjuvant ADT (HR, 0.57; P < .0001).
Progression of the primary tumor was found in 179 men, and progression at distant sites was found in 226 men. The 10-year cumulative incidence of local progression as a first event was 28.2% for radiotherapy alone, 15.7% for 3 months of neoadjuvant ADT (HR, 0.49; P = .0005), and 13.3% for 6 months of neoadjuvant ADT (HR, 0.45; P < .0001).
More Data to Come
The authors note that data from the RTOG 92.02 study showed that patients with high Gleason scores received the most benefit from prolonged ADT, raising the possibility that "the morbidity of long-term androgen deprivation can be restricted to men with the highest risk of progression."
Although subgroup analyses of prostate-cancer-specific mortality data in TROG 96.01 did not support this hypothesis, the authors explain that the interpretation of the trial's pathology data is limited by lack of a centralized histopathologic review.
"We hope that this trial's successor, TROG 03.04 RADAR34 — which investigates adding 12 months of adjuvant ADT, with or without 18 months of zoledronate, to 6-month neoadjuvant ADT and radiotherapy — can help resolve this possibility," they write.
The study was funded by Australian Government National Health, the Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough. The authors and the editorialist have disclosed no relevant financial relationships.

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