DURATION OF HORMONE THERAPY AND DOSE OF RT FOR PROSTATE CANCER

SAN FRANCISCO — Radiation oncologists continue to chip away at the issue of how to best manage men with intermediate- and high-risk prostate cancer.

Some of the latest data come from a Spanish randomized clinical trial, which was presented here at the American Society for Radiation Oncology (ASTRO) 56th Annual Meeting.

The investigators conclude that the most aggressive prostate cancers need to be treated in kind — with aggressive dose-escalated radiation therapy (RT) and more, not less, hormone therapy.

The trial compared hormone therapy given over 28 months (long term) with that given over 4 months (short term) in combination with high-dose conformal RT in men with intermediate- and high-risk prostate cancer.

Men with T3 disease and/or a Gleason score of 8 to 10 and/or a prostate-specific antigen level (PSA) level above 20 ng/mL were considered to be at high risk. Men with T1 or T2 disease with a Gleason score of 7 and/or a PSA level of 10 to 20 ng/mL were considered to be at intermediate risk.

The study is "pioneering" because it is the first to examine long- and short-term hormone therapy in these men in the setting of high-dose RT (median dose, 78 Gy), said lead investigator Almudena Zapatero, MD, from Hospital Universitario de la Princesa in Madrid, Spain, who presented the study on behalf of the Spanish Group of Clinical Research in Radiation Oncology.

Overall, in the 355-patient study (median follow-up, 63 months), the 5-year rate of biochemical disease-free survival, one of the study's primary end points, was better with long-term than with short-term hormone therapy.

But a closer look at the data revealed that the bulk of the benefit was in the 189 high-risk patients, not in the 166 intermediate-risk patients, Dr. Zapatero reported.

This led the investigators to conclude that high-risk patients — but not intermediate-risk patients — should be treated with high-dose RT and long-term hormone therapy.

Table 1. Five-Year Rate of Biochemical Disease-Free Survival

Risk Group	Long-Term Hormones, %	Short-Term Hormones, %	PValue
High	88.0	75.9	.058
Intermediate	91.8	87.5	.17

Although it was not significant, the difference in the rate of biochemical disease-free survival was much more impressive with long-term than with short-term hormone therapy.

But it is the overall survival data that really distinguish the benefit of long-term hormones in high-risk men.

For men with high-risk disease, the 5-year rate of overall survival — the secondary end point — was significantly better with long-term than with short-term hormone therapy group (96.1% vs 81.5%; P = .01).

For men with intermediate-risk disease, the 5-year overall survival results were nearly identical for long-term and short-term hormone therapy.Importantly, toxicity — the other primary end point — was comparable in the long-term and short-term groups.

Thus, for men with high-risk prostate cancer treated with long-term hormone therapy, the combination of the results on biochemical disease-free survival (nearly statistically significant), overall survival (statistically significant), and toxicity (not increased significantly) mean that a long course of hormones is an advisable treatment strategy, Dr. Zapatero noted.

However, longer follow-up is needed to confirm the results, she added.

Study Addresses an "Unknown" Question

This study addresses a question that "has really remained unknown," said Anthony D'Amico, MD, PhD, from Harvard Medical School in Boston. He acted as study discussant during one of the meeting's plenary sessions.

Dr. D'Amico said that other studies have looked at these risk groups and the length of hormone therapy, but they used lower doses of radiation.

At a meeting press conference, Colleen Lawton, MD, from the Medical College of Wisconsin in Milwaukee, gave an overview of the treatment of prostate cancer, especially high-risk disease, with RT and hormone therapy.

"We have shown over time that increasing the [RT] dose improves outcomes" and have "shown that adding hormone therapy improves outcomes," she said.

The doses of both RT and hormones have also been "bumped up" over time in various studies. This begged the question of whether or not hormone therapy was needed when the RT is "dose-escalated [as in the current study]," she stated.

The answer is yes, "we still need long-term hormone therapy, especially for the most aggressive [prostate] cancers," said Dr. Lawton, who is also chair of the board of directors for ASTRO.But the length of long-term hormone therapy continues to be debated. "Eighteen months may be the new amount of long-term hormone therapy that we need," she said, referring to data from Canada reported in 2013.

Dr. Lawton also provided a perspective on how high-risk prostate cancer patients are currently managed in the United States.

"High-risk prostate cancer patients, in general, get radiation therapy and hormone therapy, but the question is what dose are they getting. I think many are getting dose-escalation, but not all," she summarized.

These results "will push [high-risk] patients to get dose-escalation," said Dr. Zapatero.

She also addressed the number of months of hormone therapy really needed to achieve the desired results in men with high-risk disease.

Long-term hormone therapy "needs to be even further tailored" in high-risk prostate cancer, Dr. Zapatero said. For example, the length of therapy should eventually be decided by disease characteristics. If a man's cancer is only T3, then perhaps 18 months of hormones will be enough. But if a man also has a Gleason score above 8 and a high PSA, then longer hormone therapy might be needed.

Issues in the management of high-prostate cancer are likely to become more important to clinicians in the future, said Dr. Lawton.

She explained that, currently, 20% to 25% of prostate cancers are high risk. But with PSA testing likely to decline substantially in the United States, clinicians will be seeing more advanced cancer in the future.Toxicity Results

This study involved 355 men recruited from 9 cancer centers in Spain from 2006 to 2010. The patients had no lymph node involvement or metastases or unfavorable risk factors (cT1c to T3aN0M0 prostate cancer), and all had PSA levels below 100 ng/mL.

All patients received 4 months of neoadjuvant and concomitant hormone therapy plus high-dose RT. Practically, this meant that hormone therapy began prior to radiation to reduce tumor size.

Patients were randomized to 1 of 2 groups: 177 patients received subcutaneous adjuvant goserelin (Zoladex), a luteinizing-hormone-releasing hormone analogue, for 24 months (long-term group); and 178 patients received only 4 months of concomitant RT hormone therapy (short-term group).

There was a comparable number of men each from risk category in the 2 hormone therapy groups. There were 85 intermediate-risk patients in the long-term group and 81 in the short-term group. There were 92 high-risk patients in the long-term group and 97 in the short-term group.

Dr. Zapatero reported that acute RT toxicity and late RT toxicity were not significantly different between the hormone therapy groups.

Table 2. RT Toxicity

Grade of RT Toxicity	Long-Term Hormones, %	Short-Term Hormones, %	P Value
Acute
Rectal toxicity >2	10.1	11.8	1.0
Urinary toxicity >2	27.3	22.9	.721
Late
Rectal toxicity >2	20.4	15.3	.547
Urinary toxicity >2	16.8	17.1	1.0

All of the toxicities in the long-term hormone therapy group resolved, except 1 case of urinary obstruction requiring a catheter. And all of the toxicities in the short-term group resolved, except 1 case of urinary stenosis and 1 case of urinary incontinence.

The authors have disclosed no relevant financial relationships. Dr. D'Amico reports a number of financial ties to industry. Dr. Lawton reports receiving honoraria from Elsevier, a publishing company.

American Society for Radiation Oncology (ASTRO) 56th Annual Meeting: Abstract PL-02. Presented September 15, 2014.