Studies Crystallize Variable Impact of ADT-RT Combination Therapy

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Howard Sandler, MD, MS, reviews evidence on hormonal and radiation therapies during his IPCC presentation.

The results of several long-term clinical trials published last year clarify the role of combination androgen-deprivation therapy (ADT) and radiation therapy (RT) in the treatment of men with prostate cancer, particularly in the intermediate-risk category, according to Howard Sandler, MD, MS.

During his presentation at IPCC, Sandler indicated that the data underscore the importance of keeping RT in treatment regimens in intermediate and high-risk patients at a time when advances in hormonal therapies have made those options increasingly attractive.

Sandler is chair of Cancer Therapeutics and professor and chair of the Department of Radiation Oncology at Cedars-Sinai Medical Center in Los Angeles, California. He also has played a leading role in the Radiation Therapy Oncology Group (RTOG) and served as a coauthor of the potentially practice-changing RTOG 94- 08 study, which showed that intermediate risk patients experienced a moderate improvement in survival when receiving both ADT and RT.

RTOG 94-08 sought to evaluate the impact of short-term ADT given before and during RT in 1979 patients with early, localized prostate cancer, defined as stage T1b/c or T2a/b and a prostate-specific antigen (PSA) level ≤20 ng/mL. Participants were randomized to receive either RT alone or RT with four months of total androgen suppression (two months before and two months during RT).

In all, the 10-year overall survival (OS) rate was 62% among those who received combination therapy compared with 57% in the radiotherapy-alone group, according to results published in The New England Journal of Medicine in July.¹

Clinical Decision Making

Low-Risk Patients

• ADT never shown to improve survival
• Control rates very good with dose-escalated RT alone

Intermediate-Risk Patients

• Control rates good with dose-escalated RT alone BUT...
• RTOG 94-08 showed survival benefit with addition of short-term ADT to RT 66 Gy
• Detailed discussion with patients regarding risks/benefits of a short course of ADT
• RTOG 08-15-1st multi-institutional phase III trial to integrate dose-escalation with ADT (6 months)

High-Risk Patients

• Standard remains RT + long-term ADT

Sandler H. Radiation therapy for high risk prostate cancer. Presented at 5th Annual Interdisciplinary Prostate Cancer Congress (IPCC); March 31, 2012; New York, NY.

Short-Term ADT for Intermediate Group

Analysis by risk group, however, showed that most of the benefit was reaped by those with an intermediate risk, with participants in that arm experiencing a 61% OS with combination therapy versus 54% with RT alone.

By contrast, the study found that low-risk and high-risk patients experienced OS gains that were not statistically significant. For the lowrisk group, the OS advantage was 67% with the combination therapy versus 64% for RT alone; for the high-risk group, it was 53% for the combination versus 51% for RT alone. Findings of other clinical trials support longer-term use of ADT in high-risk patients, the authors noted.

“What this trial did was firmly establish the role of short-term hormone therapy in combination with radiation for intermediate-risk prostate cancer patients,” Sandler said. “Intermediate-risk patients who may have received radiation therapy alone now are being encouraged to pursue combination therapy with androgen ablation because of the results of this randomized trial.”

Sandler said the results build upon several studies that have shown a clinical advantage to using a short-term combination of ADT with RT in intermediate- and high-risk patients. The results of the TROG 96.01 trial, published in Lancet Oncology last year, showed that six months of neoadjuvant ADT with RT reduced PSA progression (HR = 0.57; confidence interval [CI], 0.46-0.72; P < .0001) and local progression (HR = 0.45; CI, 0.30-0.66; P = .0001), and improved event-free survival compared with RT alone (HR = 0.51; CI, 0.42-0.61; P < .0001).²

Longer ADT Helps High-Risk Patients

While short-term ADT appeared to benefit intermediate-risk patients, higher-risk patients appear to benefit from longer-term hormonal therapy. For example, in the RTOG 85-31 study, the absolute survival rate after a median follow-up of 10 years was significantly higher in patients receiving adjuvant hormonal therapy plus RT (49%) compared with patients who received RT alone (39%).³ A secondary analysis showed that patients who received hormone therapy for at least five years benefited more than patients who received it for less than five years.⁴

Other studies have supported the use of continuous ADT in high-risk patients. In a National Cancer Institute of Canada study, high-risk patients treated with continuous ADT plus RT showed an overall survival advantage of 74% compared with 66% in patients being treated with ADT alone after seven years of follow-up.⁵

Despite these studies supporting the use of combination therapy in high-risk patients, Sandler cited a study that showed that more than 40% of these patients received hormone therapy alone as a primary treatment.⁶

“Many men with high-risk prostate cancer, even today, are being treated with hormone therapy alone, and thus probably being undertreated for their locally advanced disease,” Sandler said. “Given that we know that adding radiation therapy…can benefit men with high-risk localized prostate cancer, I strongly believe that primary hormonal therapy should rarely be used as long as men have a life expectancy otherwise of more than five years.”

References

1. Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and shortterm androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365(2):107-118.
2. Denham JW, Steigler A, Lamb DS, et al. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011;12(5):451-459.
3. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate cancer carcinoma—long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005;61(5):1285-1290.
4. Souhami L, Bae K, Pilepich M, Sandler H. Impact of the duration of adjuvant hormonal therapy in patients with locally advanced prostate cancer treated with radiotherapy: a secondary analysis of RTOG 85-31. J Clin Oncol. 2009;27(13):2137-2143.
5. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378(9809):2104-2111.
6. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010;28(7):1117-1123.