Neoadjuvant and or Adjuvant Androgen Suppression for Localized Prostate Cancer
Neoadjuvant and/or adjuvant androgen suppression has become a relatively routine approach for the treatment of men with localized prostate cancer who receive treatment with EBRT or brachytherapy and are considered to be at high or intermediate-risk for recurrence. The decision to use androgen suppression therapy involves many issues, including optimal timing in regards to other treatment modalities, specific extent of disease in which androgen suppression makes the most sense when weighing outcomes and side effects, patient characteristics that define the optimal candidate for androgen suppression use, and specific schedules or regimens of hormonal therapy. All of these issues remain areas of debate, with much discussion surrounding them at the 2003 ASTRO meeting. In regards to androgen suppression therapy in localized prostate cancer, physicians at the meeting expressed differing detailed views of the precise stage at which to initiate hormonal therapy, optimal duration of treatment with hormonal therapy, and timing in regards to radiation therapy. However, with the results from prospective clinical trials maturing, the areas of debate are slowly being answered. Just as importantly, results from these trials are providing a platform from which the most appropriate questions can be asked and from which future clinical trials can be designed in order to provide definitive answers as to the optimal use of androgen suppression therapy in the treatment of localized prostate cancer.
Adjuvant Androgen Suppression
Although results from randomized clinical trials demonstrated superiority of the addition of adjuvant androgen suppressive therapy to radiation therapy in localized prostate cancer,1,2 particularly in those at high-risk, two retrospective studies presented at ASTRO 2003 questioned the routine use of adjuvant androgen suppression in this group of patients.3,4 These two studies prompted much discussion at the meeting as they were at odds with all of the randomized trials performed to date, which have shown benefit from androgen suppression. The discussions centered on the difficulty of evaluating androgen suppression in retrospective studies, during which only high-risk patients tend to be given hormonal therapy. Physicians at this meeting were not willing to change their approach to the management of prostate cancer based on these two retrospective studies, but agreed that information from these studies could help to form the basis of further prospective randomized trials.
One important randomized clinical trial that supported the use of adjuvant hormone suppression therapy in addition to EBRT in high-risk patients with localized prostate cancer was conducted by affiliates of RTOG. The results presented were the long-term results of RTOG 85-31.1 This study was a randomized trial evaluating adjuvant goserelin (Zolodex®) in 977 men with clinical T3 stage with gross disease, positive margins or positive lymphatic involvement. Surgery patients were also eligible for this study if they met the above criteria. Patients received 44-46 Gy to the pelvis and 65 Gy to the prostate. Following EBRT, half the patients received adjuvant Zolodex® for 2 years. The average follow-up for this study was over 7 years. The authors reported “Adjuvant androgen suppression has resulted in significant improvement in all endpoints including absolute survival.” The 10-year absolute survival in the group receiving adjuvant Zolodex® was 53% compared to 38% for the control group, but this difference only emerged after 8 years of follow-up. This demonstrates the need for very long follow-up in trials evaluating treatment for localized prostate cancer. Adjuvant Zolodex® reduced local failures from 39% to 23%, and distant metastatic disease from 39% to 25%. Furthermore, disease-specific mortality was decreased from 22% to 17% with adjuvant Zolodex®. This long-term follow-up provides proof of principle of the use of adjuvant androgen suppression in conjunction with EBRT for the treatment of localized prostate cancer. However, the authors pointed out that the effect of androgen suppression was greatest in the highest risk patients, with no benefit for patients with a Gleason score of 2-6.
Another large randomized clinical trial presented at ASTRO also supported the use of adjuvant androgen suppression in men with localized prostate cancer who were receiving radiation therapy. Payne, et al. from the UK presented a 3-year follow-up of The Early Prostate Cancer (EPC) program sponsored by AstraZeneca.2 This study involved over 8,000 men from 47 centers from around the world. All had localized or locally advanced prostate cancer and were treated with radiation therapy, surgery, or watchful waiting. This analysis included the men who were treated with radiation therapy. The radiation arm included over 3,000 men who were randomly allocated to receive adjuvant Casodex® or placebo. Casodex® was given in an intermittent fashion, with 8 months of therapy followed by an average of 9 months off therapy. Patients receiving Casodex® had a 58% improvement in biochemical PSA failure and a 37% reduction in PFS compared to patients receiving placebo. Results of data were presented in a manner referred to as “event-time ratio” (ETRO). Using this calculation, 10% of patients in the placebo arm progressed in 2.9 years, compared to 2.2 years for the Casodex® group. Benefit appeared to be the greatest in patients with locally advanced disease, with 20% of patients progressing in 3.2 years in the control group, compared to 4.9 years in the Casodex® group.
Researchers from the William Beaumont Hospital in Royal Oak Michigan and Kiel University conducted one of the retrospective studies that failed to show a benefit from adjuvant androgen suppression.3 These researchers performed a retrospective analysis of over 500 patients treated for localized prostate cancer with unfavorable features. Patients were treated with high-dose EBMT and brachytherapy with or without a short course of adjuvant or concurrent androgen deprivation for 6 months or less. Approximately a third of these patients received androgen suppression. Progression-free survival was 73% for the patients who received androgen suppression, and 89% for those who did not receive androgen suppression. There were more metastatic disease recurrences in the androgen suppression group, compared to those who did not receive androgen suppression. Cause-specific survival was reported to be 97% in the non-hormonal group, compared to 91% in the androgen suppression group. Based on the analysis of these results, the authors concluded that there was no benefit, but possible harm, from adjuvant androgen suppression in addition to radiation therapy in these patients with localized prostate cancer.
In another study, researchers reported on the second retrospective study that did not support the use of androgen suppression in patients with localized prostate cancer being treated with radiation.4 This study was an evaluation of 2,470 patients with localized prostate cancer who had received brachytherapy as primary treatment. Of these patients, 524 had been treated with neoadjuvant hormonal therapy, in an attempt to shrink the cancer prior to seed implantation. Taking into account appropriate risk factors, data indicated a cause-specific survival of 88% for patients who had not received hormonal therapy and 78% for those who had received hormonal therapy. Surprisingly, overall survival was only reported at 15% for those who received hormonal therapy, compared to 44% for those who had not received hormonal therapy.
Again, information gathered from these two latter retrospective studies may provide useful guidance into future studies and clinical applications. However, results from randomized clinical trials continue to demonstrate superiority of the addition of adjuvant androgen suppression therapy to radiation therapy in patients with localized prostate cancer. Even long-term follow-up and a trial including several thousand patients clearly indicate improved outcomes for patients with localized prostate cancer treated with adjuvant androgen suppressive therapy in addition to radiation therapy.
Toxicities Associated with Adjuvant Androgen Deprivation
Although outcomes may be improved with the use of adjuvant androgen deprivation in localized prostate cancer patients who are being treated with primary radiation therapy, acute and long-term toxicities need to be weighed against these outcomes. Side effects become particularly important when deciding upon hormone suppression for low or intermediate-risk patients, as these groups of patients may not derive the extent of benefit from hormone therapy as high-risk patients.
Researchers from Fox Chase reported that late morbidity was increased with the use of androgen suppression in the treatment of localized prostate cancer.5 Outcomes of 1,203 patients with localized prostate cancer treated with 3D-EBRT with or without androgen deprivation therapy were analyzed in terms of toxicities associated with treatment. Patients treated with androgen suppression therapy were treated with either short-term androgen deprivation (6 months or less), long-term androgen deprivation (>6 months of androgen deprivation), or no androgen deprivation. At 5 and 10 years, grade II GU and GI toxicities associated with androgen deprivation therapy persisted in nearly 20% of patients. Furthermore, the incidence of diabetes was increased in the group of patients who were treated with androgen deprivation therapy. Both the short and long-term hormone therapy regimens were associated with late morbidity. Obviously, physicians not only need to address possible early side effects associated with androgen deprivation with their patients, but also the possibility of late side effects that could persist 10 years or more.
Intermittent Androgen Suppression for Metastatic Prostate Cancer
Androgen suppression is one of the most commonly used treatment modalities for patients with metastatic prostate cancer. Research is now focused on different schedules and regimens of hormone therapy in the hopes of improving outcomes, quality of life of a patient, or both. Intermittent androgen suppression (IAS), in which hormone therapy is periodically stopped and then re-started, is a type of schedule being evaluated in the metastatic setting. There are a few different rationales behind the use of IAS. The first is to decrease toxicities associated with hormone suppressive therapy, such as loss of libido, weight gain, osteoporosis, fractures, and anemia. In addition, the use of IAS may allow for the immediate institution of androgen suppression rather than delayed institution, without committing to indefinite treatment at the onset of therapy. Furthermore, IAS may potentially restore apoptosis during the time in which therapy is stopped, which would delay hormone refractoriness. Intermittent androgen suppression has been explored in phase II trials in patients with various stages of prostate cancer.7-9 There are ongoing phase III trials comparing IAS to standard continuous administration of androgen suppression, but these results will not be available for several years.
Researchers from the Ottawa Regional Cancer Center reported on a trial evaluating IAS in the treatment of 95 patients with recurrent prostate cancer following radiation therapy.6 Eligible patients had biochemical recurrence, local recurrence, or minimal metastatic disease. Initial therapy was total androgen suppression for 8 months with lupron and nilutamide. Treatment was restarted when PSA levels rose to over 10 ng/ml, or if there was a clinical recurrence. The median duration off therapy was reported to be 9 months, with a range of 1-56 months. IAS was continued until treatment failed to normalize PSA levels, or there was evidence of disease progression. Treatment failure, defined as hormone refractoriness, occurred at a median of 4 years. Testosterone recovery was documented in 61% of patients and sexual function was recovered in approximately half of patients. In addition, half the patients had improvement of anemia. There was also significant cost savings with IAS compared to continuous androgen suppression. The authors of this study concluded that IAS is a feasible hormone therapy schedule for the treatment of metastatic prostate cancer.
This and other studies suggest that IAS is a reasonable approach for the treatment of patients requiring androgen suppression if they are not being entered into ongoing randomized trials. This approach (IAS) has as much rationale going for it as the standard approach of continuous androgen suppression and has the potential for being much less toxic. IAS is associated with significant cost savings for this very expensive form of palliative therapy.
Conclusion
Neoadjuvant and adjuvant androgen therapy appears to improve outcomes of patients with intermediate or high-risk localized prostate cancer who are being treated with radiation therapy. However, the exact schedule of administration (i.e. long versus short, or continuous versus intermittent) of hormone therapy, the exact stage at which to initiate hormone therapy, and/or schedules with combination chemotherapy can only be optimally defined with further study. Direct comparisons of these unanswered issues are ongoing, and results are eagerly awaited. In the metastatic setting, it appears that the use of intermittent rather than continuous administration of androgen suppression decreases side effects, but again, only current ongoing randomized trials can determine if survival is compromised by this approach.
References
1. Pilepich MV, Winter K, Lawton C, et al. Androgen Suppression Adjuvant to Radiotherapy in Carcinoma of the Prostate. Long-Term Results of Phase III RTOG Study 85-31. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 82:S172.
2. Payne H, Tyrrell C, See WA, et al. Bicalutamide 150 mg as Adjuvant to Radiotherapy Significantly Increases Progression-Free survival in Early Prostate Cancer. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 83:S173.
3. Martinez A, Galalae R, Mitchell C, et al. Lack of Benefit at 5 Years from a Short Course of Neoadjuvant/Concurrent Androgen Deprivation for Unfavorable Prostate Cancer Patients Treated to a High Total Radiation Dose. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 85:S175. 5.
4. Beyer DC and McKeough T, Impact of Prior Hormonal Therapy on Overall and Cancer-Specific Survival Following Permanent Prostate Brachytherapy. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 87:S176.
5. Feigenberg SJ, Hanlon AL, Horwitz EM, et al. Androgen Deprivation Increases Late Morbidity in Prostate Cancer Patients Treated with 3D Conformal Radiation Therapy. Proceedings of the 45th Annual ASTRO meeting. International Journal of Radiation Oncology Biology Physics 2003;57, No.2, Supplement. Abstract number 86:S176.
6. Malone S, Remco D, Gad P, et al. Mature Phase II Study of Intermittent Androgen Suppression (IAS) in Prostate Cancer (PC): Efficacy and Long-Term Effect Profile. Proceedings of the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology. International Journal of Radiation Oncology Biology Physics 2003;57, Number 2, Supplement, Abstract Number 84:S174.
7. De La Taille A, Zerbib M, Conquy S, et al. Intermittent Androgen Suppression in Patients with Prostate Cancer. British Journal of Urology International 2003;91:18-22.
8. Pether M, Goldenberg SL, Bhagirath K, et al. Intermittent Androgen Suppression in Prostate Cancer: An Update of the Vancouver Experience. Canadian Journal of Urology 2003;20:1809-1814.
9. Albrecht W, Collette L, Fava C, et al. Intermittent Maximal Androgen Blockade in Patients with Metastatic Prostate Cancer: An EORTC Feasibility Study. European Urology 2003;44:505-511.
