The Current Role of Androgen Deprivation in Patients Undergoing Dose-Escalated External Beam Radiation Therapy for Clinically Localized Prostate Cancer
Purpose. To review existing literature on the role of androgen deprivation therapy (ADT) with dose escalated radiation therapy. Methods and Materials. A PubMed search was undertaken to identify relevant articles. Results. Multiple recent studies were identified examining the role of ADT in the current era of radiation dose-escalation. Among the reviewed studies, varying radiation doses and techniques, ADT regimens, and patient selection criteria were utilized. Conflicting results were reported, with some studies demonstrating a benefit of delivering a higher radiation dose with ADT. Other studies failed to show significant benefits with the addition of ADT to dose-escalated RT. Conclusions. The benefit of adding ADT to dose-escalated RT is still uncertain. Prospective randomized trials, several of which are ongoing, are necessary to more adequately examine this issue. In the interim, physicians and patients should continue to utilize the existing data to weigh the risks and benefits of each approach to therapy. 1. Introduction Significant improvements in outcome have been achieved in the treatment of prostate cancer (PC) over the last couple of decades. Advancements in external beam technology, such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) have allowed for dose escalation, with improvements in biochemical failure and rate of distant metastases (though no overall survival (OS) benefits have yet been demonstrated), without an accompanying increase in short- and intermediate-term toxicity [1–3]. We have also learned through multiple phase III randomized trials that the addition of ADT to external beam radiation therapy (EBRT) in unfavorable or locally-advanced cancers leads to improvements in disease-free survival (DFS), and prostate cancer-specific survival, as well as in OS (Table 1) [4–14]. However, in all of these studies, radiation doses ≤70？Gy were delivered, which are below the current standard doses used. In addition, it is increasingly recognized that ADT may be associated with acute and long-term toxicity. One controversy that currently exists in the radiation community is the role of ADT with dose-escalated radiation therapy in intermediate-risk and high-risk patients. This paper is intended to summarize existing data looking at this issue. In addition, a brief review of toxicity of hormonal therapy will be discussed. Table 1 2. Materials and Methods A PubMed literature search was undertaken, and relevant articles were reviewed. Search words and phrases included “dose-escalated radiation therapy
References
[1]
D. A. Kuban, S. L. Tucker, L. Dong et al., “M.D. Anderson randomized dose-escalation trial for prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 70, no. 1, pp. 67–74, 2008.
[2]
A. L. Zietman, M. L. DeSilvio, J. D. Slater et al., “Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial,” Journal of the American Medical Association, vol. 294, no. 10, pp. 1233–1239, 2005.
[3]
S. T. H. Peeters, W. D. Heemsbergen, P. C. M. Koper et al., “Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy,” Journal of Clinical Oncology, vol. 24, no. 13, pp. 1990–1996, 2006.
[4]
J. A. Efstathiou, K. Bae, W. U. Shipley et al., “Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31,” Journal of Clinical Oncology, vol. 27, no. 1, pp. 92–99, 2009.
[5]
M. V. Pilepich, K. Winter, M. J. John et al., “Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate,” International Journal of Radiation Oncology Biology Physics, vol. 50, no. 5, pp. 1243–1252, 2001.
[6]
G. E. Hanks, T. F. Pajak, A. Porter et al., “Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology group Protocol 92-02,” Journal of Clinical Oncology, vol. 21, no. 21, pp. 3972–3978, 2003.
[7]
A. V. D'Amico, J. Manola, M. Loffredo, A. A. Renshaw, A. DellaCroce, and P. W. Kantoff, “6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial,” Journal of the American Medical Association, vol. 292, no. 7, pp. 821–827, 2004.
[8]
A. V. D'Amico, M. H. Chen, A. A. Renshaw, M. Loffredo, and P. W. Kantoff, “Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial,” Journal of the American Medical Association, vol. 299, no. 3, pp. 289–295, 2008.
[9]
C. A. Lawton, M. DeSilvio, M. Roach et al., “An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions,” International Journal of Radiation Oncology Biology Physics, vol. 69, no. 3, pp. 646–655, 2007.
[10]
J. W. Denham, A. Steigler, D. S. Lamb et al., “Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial,” Lancet Oncology, vol. 6, no. 11, pp. 841–850, 2005.
[11]
M. Bolla, T. M. De Reijke, G. Van Tienhoven et al., “Duration of androgen suppression in the treatment of prostate cancer,” New England Journal of Medicine, vol. 360, no. 24, pp. 2516–2527, 2009.
[12]
C. U. Jones, D. Hunt, D. G. McGowan et al., “Radiotherapy and short-term androgen deprivation for localized prostate cancer,” New England Journal of Medicine, vol. 365, no. 2, pp. 107–118, 2011.
[13]
M. Bolla, G. Van Tienhoven, P. Warde et al., “External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study,” The Lancet Oncology, vol. 11, no. 11, pp. 1066–1073, 2010.
[14]
J. Crook, C. Ludgate, S. Malone et al., “Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer,” International Journal of Radiation Oncology Biology Physics, vol. 73, no. 2, pp. 327–333, 2009.
[15]
D. P. Dearnaley, M. R. Sydes, J. D. Graham et al., “Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial,” Lancet Oncology, vol. 8, no. 6, pp. 475–487, 2007.
[16]
M. J. Zelefsky, Y. Yamada, M. A. Kollmeier, A. M. Shippy, and M. A. Nedelka, “Long-term outcome following three-dimensional conformal/intensity-modulated external-beam radiotherapy for clinical stage T3 prostate cancer,” European Urology, vol. 53, no. 6, pp. 1172–1179, 2008.
[17]
M. A. Kollmeier and M. J. Zelefsky, “What is the role of androgen deprivation therapy in the treatment of locally advanced prostate cancer?” Nature Clinical Practice Urology, vol. 5, no. 11, pp. 584–585, 2008.
[18]
A. Zapatero, F. Valcárcel, F. A. Calvo et al., “Risk-adapted androgen deprivation and escalated three-dimensional conformal radiotherapy for prostate cancer: does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR study,” Journal of Clinical Oncology, vol. 23, no. 27, pp. 6561–6568, 2005.
[19]
A. Zapatero, P. Ríos, A. Marín, R. Mínguez, and F. García-Vicente, “Dose escalation with three-dimensional conformal radiotherapy for prostate cancer. Is more dose really better in high-risk patients treated with androgen deprivation?” Clinical Oncology, vol. 18, no. 8, pp. 600–607, 2006.
[20]
A. Zapatero, F. García-Vicente, C. Martín De Vidales et al., “Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease?” International Journal of Radiation Oncology Biology Physics, vol. 81, no. 5, pp. 1279–1285, 2011.
[21]
A. Zapatero, A. Guerrero, X. Maldonado et al., “Long-term versus short-term androgen deprivation combined with high-dose radiotherapy for localized prostate cancer: a Spanish multicenter phase III trial,” Journal of Clinical Oncology, vol. 28, supplement, abstract e15036, 2010.
[22]
S. L. Liauw, W. M. Stadler, D. Correa, R. R. Weichselbaum, and A. B. Jani, “Dose-escalated radiotherapy for high-risk prostate cancer: outcomes in modern era with short-term androgen deprivation therapy,” International Journal of Radiation Oncology Biology Physics, vol. 77, no. 1, pp. 125–130, 2010.
[23]
R. K. Valicenti, K. Bae, J. Michalski et al., “Does hormone therapy reduce disease recurrence in prostate cancer patients receiving dose-escalated radiation therapy? An analysis of Radiation Therapy Oncology Group 94-06,” International Journal of Radiation Oncology Biology Physics, vol. 79, no. 5, pp. 1323–1329, 2011.
[24]
D. Krauss, L. Kestin, H. Ye et al., “Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer,” International Journal of Radiation Oncology, Biology, Physics, vol. 80, no. 4, pp. 1064–1071, 2010.
[25]
R. D. Tendulkar, C. A. Reddy, K. L. Stephans et al., “Redefining high-risk prostate cancer based on distant metastases and mortality after high-dose radiotherapy with androgen deprivation therapy,” Int J Radiat Oncol Biol Phys, vol. 82, no. 4, pp. 1397–1404, 2012.
[26]
M. H. Stenmark, K. Blas, S. Halverson, H. M. Sandler, F. Y. Feng, and D. A. Hamstra, “Continued benefit to androgen deprivation therapy for prostate cancer patients treated with dose-escalated radiation therapy across multiple definitions of high-risk disease,” International Journal of Radiation Oncology Biology Physics, vol. 81, no. 4, pp. e335–e344, 2011.
[27]
P. L. Nguyen, M. H. Chen, C. J. Beard et al., “Radiation with or without 6 months of androgen suppression therapy in intermediate and high risk clinically localized prostate cancer: a postrandomization analysis by risk group,” International Journal of Radiation Oncology Biology Physics, vol. 77, no. 4, pp. 1046–1052, 2010.
[28]
P. L. Nguyen, Y. Je, F. A.B. Schutz et al., “Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials,” Journal of the American Medical Association, vol. 306, no. 21, pp. 2359–2366, 2011.
[29]
M. J. Zelefsky, H. Chan, M. Hunt, Y. Yamada, A. M. Shippy, and H. Amols, “Long-Term Outcome of High Dose Intensity Modulated Radiation Therapy for Patients With Clinically Localized Prostate Cancer,” Journal of Urology, vol. 176, no. 4, pp. 1415–1419, 2006.
[30]
A. Nanda and A. V. D'Amico, “Combined radiation and hormonal therapy or dose escalation for men with unfavourable-risk prostate cancer: an evidence-based approach using a synthesis of randomized clinical trials,” British Journal of Urology International, vol. 102, no. 10, pp. 1366–1368, 2008.
[31]
J. L. Speight and M. Roach III, “Radiotherapy in the management of clinically localized prostate cancer: evolving standards, consensus, controversies and new directions,” Journal of Clinical Oncology, vol. 23, no. 32, pp. 8176–8185, 2005.
[32]
C. Huggins and C. V. Hodges, “Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate,” Cancer Research, vol. 1, pp. 239–297, 1941.
[33]
Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer, http://clinicaltrials.gov/ct2/show/NCT01368588/.
[34]
Radiation Therapy in Treating Patients Receiving Hormone Therapy for Prostate Cancer, http://clinicaltrials.gov/ct2/show/NCT00967863/.
[35]
Study on the Role of Hormonal Treatment for Two Dosage Levels of Prostate Radiation Therapy Versus Prostate Radiation Therapy Alone, http://clinicaltrials.gov/ct2/show/NCT00223145/.
[36]
Triptorelin, Flutamide, and External-Beam Radiation Therapy or External-Beam Radiation Therapy Alone in Treating Patients With Stage II or Stage III Prostate Cancer, http://www.clinicaltrials.gov/ct2/show/NCT00104741/.
[37]
Radiation Therapy With or Without Androgen-Deprivation Therapy in Treating Patients With Prostate Cancer, http://clinicaltrials.gov/ct2/show/NCT00936390/.
