Summary by Dr. Luis Souhami MD – McGill University Health Centre
In our paper we critically reviewed major publications that evaluated the use of radiation therapy (RT) combined with androgen deprivation for localized prostate cancer. Also, a brief summary of some important preclinical studies was made in order to reinforce a better understanding of the biological basis for this approach. For didactic purposes, we have clustered prospective randomized trials in two major groups: one including studies basically testing hormonal therapy before RT (neoadjuvant therapy) and other using hormonal therapy concomitantly and/or after RT. Based on this scheme, we endeavoured to properly define most appropriate treatment recommendations for each risk category.
For patients with low-risk disease, given the lack of randomized trials specifically designed for this group of patients, clinical benefits from combined treatment remain unknown. Currently, we have no evidence that adding hormonal therapy to this group of patients makes any difference in outcomes. For patients with high-risk disease, the advantage of the combined treatment is clearly supported by level I evidence. The classical study by Bolla et al2. (EORTC 22863) has shown an improved 5-year overall survival of 16% for patients receiving androgen deprivation for 36 months. Pilepich et al3. (RTOG 8531) have also presented an increased overall survival of 10% at 10 years when patients received adjuvant hormonal therapy indefinitely or until signs of disease progression.
The usefulness of short-term hormonal therapy in association with radiotherapy for intermediate-risk patients is still debatable, particularly in the context of dose-escalated RT, but hopefully this question will be answered by the recently closed PCS 3 Quebec trial (Dr. A. Nabid, principal investigator) or by the ongoing RTOG 0815 (Dr. A. Martinez, principal investigator). Uro-oncologists who favour the use of androgen deprivation with RT for intermediate-risk disease can justify its approach based on D’Amico et al4. study and the recent results from RTOG 94085 protocol. Nevertheless, these trials were not exclusive for intermediate risk patients and both have used RT doses lower than the current standard.
Many other issues are under investigation including the optimal timing and duration of hormonal therapy. The latter is particularly important given the potential hormone-related toxicity. A recent EORTC randomized trial6 comparing 6 months versus 36 months of androgen suppression for patients with locally advanced disease showed an inferior outcome for the shorter hormonal duration. The closed PCS 4 randomized trial (Dr. A. Nabid, principal investigator) compared 18 months versus 36 months of hormonal therapy and the results of this important study should be forthcoming soon. Recently, Cuppone et al.7 carried out a meta-analysis of randomized trials comparing a shorter versus longer hormonal treatment duration. The longer hormonal suppression significantly decreased biochemical, local and distant failures with a trend for cancer specific survival. Adding uncertainty to the optimal duration of the hormonal suppression is the reported result of a hypothesis-generating secondary analysis performed on the RTOG 85-31 protocol8 in which patients receiving hormonal therapy for 5 years or longer had improved outcomes compared to those receiving less than 5 years. Similar improvement in outcomes has been seen in the management of breast cancer patients receiving hormonal manipulation for a longer period. Can prostate cancer patients achieve comparable benefits? Or is it possible to tailor treatment duration based on individual characteristics, such as biochemical response to hormonal therapy at specific time points? PSA response was recently demonstrated to be a more important predictor of outcomes than treatment duration and other tumor characteristics in two other hypothesis-generating analyses 9,10.
Adverse outcomes from hormonal suppression have been recognized for many years. The consequences of utilizing such therapy for prolonged time in older men can be important and may lead to an increased rate of cardiovascular diseases, diabetes, osteoporosis, muscle wasting, anemia, etc. Keating et al.11 reviewed over 37 000 patients diagnosed with locally or regional prostate cancer through the Veterans Healthcare Administration and treated between 2001 and 2004. Their data somehow confirmed that the use of hormonal therapy has the potential to significant unintended complications with 20 and 25% of men treated developing coronary heart disease and diabetes, respectively. The authors correctly stated that “Although the risks associated with androgen deprivation therapy remain incompletely defined, the potential for harm from this treatment underscores the importance of better understanding the benefits.”
In conclusion, the combination of RT and hormonal therapy has consistently shown improvements in different clinical endpoints. However, these trials have included a heterogeneous group of patients with intermediate- and high-risk disease, different endpoints, and varied treatments schemas, making an objective interpretation of the results rather difficult. The optimal duration of the therapy, particularly in patients with high-risk disease, remains controversial. Definitely, these questions need to be answered and novel, appropriate randomized trials with a proper definition of risk stratification, anticipated benefits and harms are clearly needed in this area.
- Dal Pra A, Cury FL, Souhami L. Curr Oncol 2010;17:28-38.
- Bolla M, Gonzalez D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295-300.
- Pilepich MV, Winter K, Lawton CA et al. Androgen suppression adjuvant to definitive radiotherapy in prostate cancer – long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285-1290.
- D’Amico AV, Chen MH, Renshaw AA et al. Androgen suppression and radiation vs. radiation alone for prostate cancer: a randomized trial. JAMA 2008;299:289-295.
- McGowan D, Hunt D, Jones C, et al. Short-term Endocrine Therapy Prior to and during Radiation Therapy Improves Overall Survival in Patients with T1b-T2b Adenocarcinoma of the Prostate and PSA ? 20: Initial Results of RTOG 94-08. Int J Radiat Oncol Biol Phys. 2010;77:1.
- Bolla M, de Reijke TM, Van Tiehoven G et al. Duration of androgen suppression in the teatment of prostate cancer. N Engl J Med 2009;360:2516-2527.
- Cuppone F, Bria E, Giannarelli D et al. Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials. BMC Cancer 2010;10:675 (Epub ahead of print).
- 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; 27:2137-2143.
- Alexander A, Crook J, Jones S et al. Is biochemical response more important than duration of neoadjuvant hormonal therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- versus 8-month randomized trial. Int J Radiat Oncol Biol Phys 2010;76:23-30.
- Cury F, Hunt D, Roach M et al. PSA response after short-term hormonal therapy plus external beam radiotherapy and outcomes in patients treated on RTOG 9413. Int J Radiat Oncol Biol Phys 2010;3(supp):S124.
- Keating NL, O’Malley AJ, Friedland SJ< Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2009;102:38-45.