Key Points
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Radiation therapy for high-risk prostate cancer provides an overall survival benefit compared with conservative management with androgen deprivation therapy (ADT) alone
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The addition of long-term (2–3 years) ADT to radiation therapy for high-risk prostate cancer provides an overall survival benefit
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Dose-escalated radiation therapy improves cancer control compared with conventional radiation doses
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Ongoing research is evaluating hypofractionation, whole-pelvic radiotherapy, and combinations of newer hormonal agents with radiation as potential ways to further improve patient outcomes in high-risk prostate cancer
Abstract
The combination of radiation treatment and long-term androgen deprivation therapy (ADT) has been shown in multiple clinical trials to prolong overall survival in men with high-risk prostate cancer compared with either treatment alone. New radiation technologies enable the safe delivery of high radiation doses that improve cancer control compared with lower radiation doses. Based on the results of multiple randomized trials, clinical practice guidelines for high-risk prostate cancer recommend total radiation doses of at least 75.6 Gy, with long-term (2–3 years) ADT. Ongoing research into hypofractionated radiation treatment, whole-pelvic radiation, and combinations of radiation with novel hormonal agents could further improve cancer control and survival outcomes for patients with high-risk prostate cancer.
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References
Mohler, J. L. et al. Prostate cancer, version 2.2014. J. Natl Compr. Canc. Netw. 12, 686–718 (2014).
Widmark, A. et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 373, 301–308 (2009).
Warde, P. et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 378, 2104–2111 (2011).
Studer, U. E. et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J. Clin. Oncol. 24, 1868–1876 (2006).
Lu-Yao, G. L. et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 300, 173–181 (2008).
Thompson, I. et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J. Urol. 177, 2106–2131 (2007).
Waxman, J. et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br. Med. J. (Clin. Res. Ed.) 291, 1387–1388 (1985).
Conn, P. M. & Crowley, W. F. Jr. Gonadotropin-releasing hormone and its analogues. N. Engl. J. Med. 324, 93–103 (1991).
D'Amico, A. V. et al. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 292, 821–827 (2004).
Laverdière, J. et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J. Urol. 171, 1137–1140 (2004).
Denham, J. W. 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 Oncol. 6, 841–850 (2005).
Hanks, G. E. 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. J. Clin. Oncol. 21, 3972–3978 (2003).
Denham, J. W. 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. 12, 451–459 (2011).
Roach, M. et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J. Clin. Oncol. 26, 585–591 (2008).
Bolla, M. et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360, 103–106 (2002).
Pilepich, M. V. et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of phase III RTOG 85–31. Int. J. Radiat. Oncol. Biol. Phys. 61, 1285–1290 (2005).
Pilepich, M. V. et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85–31. J. Clin. Oncol. 15, 1013–1021 (1997).
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. 27, 2137–2143 (2009).
Horwitz, E. M. et al. Ten-year follow-up of radiation therapy oncology group protocol 92–02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J. Clin. Oncol. 26, 2497–2504 (2008).
Bolla, M. et al. Duration of androgen suppression in the treatment of prostate cancer. N. Engl. J. Med. 360, 2516–2527 (2009).
Purdy, J. A. Intensity-modulated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 35, 845–846 (1996).
Al-Mamgani, A. et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 72, 980–988 (2008).
Dearnaley, D. P. et al. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial. Lancet Oncol. 15, 464–473 (2014).
Kuban, D. A. et al. Long-term results of the, M. D. Anderson randomized dose-escalation trial for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 67–74 (2008).
Beckendorf, V. et al. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 80, 1056–1063 (2011).
Konaka, H. et al. Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial. BMC Cancer 12, 110 (2012).
Cox, J. D., Stetz, J. & Pajak, T. F. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int. J. Radiat. Oncol. Biol. Phys. 31, 1341–1346 (1995).
Sheets, N. C. et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307, 1611–1620 (2012).
Michalski, J. M. et al. Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int. J. Radiat. Oncol. Biol. Phys. 87, 932–938 (2013).
Zelefsky, M. J. et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 1124–1129 (2008).
Hoppe, B. S. et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer 120, 1076–1082 (2014).
Park, S. S. et al. Adaptive image-guided radiotherapy (IGRT) eliminates the risk of biochemical failure caused by the bias of rectal distension in prostate cancer treatment planning: clinical evidence. Int. J. Radiat. Oncol. Biol. Phys. 83, 947–952 (2012).
van Haaren, P. M. et al. Influence of daily setup measurements and corrections on the estimated delivered dose during IMRT treatment of prostate cancer patients. Radiother. Oncol. 90, 291–298 (2009).
Sanda, M. G. et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N. Engl. J. Med. 358, 1250–1261 (2008).
Wei, J. T., Dunn, R. L., Litwin, M. S., Sandler, H. M. & Sanda, M. G. Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 56, 899–905 (2000).
Kamo, N. et al. Evaluation of the SCA instrument for measuring patient satisfaction with cancer care administered via paper or via the Internet. Ann. Oncol. 22, 723–729 (2011).
Incrocci, L., Koper, P. C., Hop, W. C. & Slob, A. K. Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int. J. Radiat. Oncol. Biol. Phys. 51, 1190–1195 (2001).
Incrocci, L., Slagter, C., Slob, A. K. & Hop, W. C. A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 66, 439–444 (2006).
Pisansky, T. M. et al. Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial. JAMA 311, 1300–1307 (2014).
Brenner, D. J., Curtis, R. E., Hall, E. J. & Ron, E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 88, 398–406 (2000).
Kendal, W. S., Eapen, L., Macrae, R., Malone, S. & Nicholas, G. Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 65, 661–668 (2006).
Baxter, N. N., Tepper, J. E., Durham, S. B., Rothenberger, D. A. & Virnig, B. A. Increased risk of rectal cancer after prostate radiation: a population-based study. Gastroenterology 128, 819–824 (2005).
Nam, R. K. et al. Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol. 15, 223–231 (2014).
Bhojani, N. et al. The rate of secondary malignancies after radical prostatectomy versus external beam radiation therapy for localized prostate cancer: a population-based study on 17,845 patients. Int. J. Radiat. Oncol. Biol. Phys. 76, 342–348 (2010).
Davis, E. J., Beebe-Dimmer, J. L., Yee, C. L. & Cooney, K. A. Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study. Cancer 120, 2735–2741 (2014).
Tayek, J. A. et al. Nutritional and metabolic effects of gonadotropin-releasing hormone agonist treatment for prostate cancer. Metabolism 39, 1314–1319 (1990).
Smith, J. C. et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J. Clin. Endocrinol. Metab. 86, 4261–4267 (2001).
Smith, M. R. et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J. Clin. Endocrinol. Metab. 87, 599–603 (2002).
Berruti, A. et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J. Urol. 167, 2361–2367; discussion 2367 (2002).
Smith, M. R. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology 63, 742–745 (2004).
Eri, L. M., Urdal, P. & Bechensteen, A. G. Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia. J. Urol. 154, 100–104 (1995).
Smith, M. R., Lee, H. & Nathan, D. M. Insulin sensitivity during combined androgen blockade for prostate cancer. J. Clin. Endocrinol. Metab. 91, 1305–1308 (2006).
Dockery, F., Bulpitt, C. J., Agarwal, S., Donaldson, M. & Rajkumar, C. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin. Sci. (Lond.) 104, 195–201 (2003).
Keating, N. L., O'Malley, A. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 24, 4448–4456 (2006).
Saigal, C. S. et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 110, 1493–1500 (2007).
Keating, N. L., O'Malley, A. J., Freedland, S. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J. Natl Cancer Inst. 102, 39–46 (2010).
Tsai, H. K., D'Amico, A. V., Sadetsky, N., Chen, M. H. & Carroll, P. R. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J. Natl Cancer Inst. 99, 1516–1524 (2007).
Punnen, S., Cooperberg, M. R., Sadetsky, N. & Carroll, P. R. Androgen deprivation therapy and cardiovascular risk. J. Clin. Oncol. 29, 3510–3516 (2011).
Efstathiou, J. A. et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85–31. J. Clin. Oncol. 27, 92–99 (2009).
Nguyen, P. L. et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306, 2359–2366 (2011).
Levine, G. N. et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J. Clin. 60, 194–201 (2010).
Schow, D. A., Renfer, L. G., Rozanski, T. A. & Thompson, I. M. Prevalence of hot flushes during and after neoadjuvant hormonal therapy for localized prostate cancer. South. Med. J. 91, 855–857 (1998).
Irani, J., Salomon, L., Oba, R., Bouchard, P. & Mottet, N. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol. 11, 147–154 (2010).
Vitolins, M. Z. et al. Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. J. Clin. Oncol. 31, 4092–4098 (2013).
Loprinzi, C. L. et al. A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann. Oncol. 20, 542–549 (2009).
Potosky, A. L. et al. Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J. Clin. Oncol. 19, 3750–3757 (2001).
Lubeck, D. P., Grossfeld, G. D. & Carroll, P. R. The effect of androgen deprivation therapy on health-related quality of life in men with prostate cancer. Urology 58 (Suppl. 1), 94–100 (2001).
Rosen, R. C. et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49, 822–830 (1997).
Teloken, P. E., Ohebshalom, M., Mohideen, N. & Mulhall, J. P. Analysis of the impact of androgen deprivation therapy on sildenafil citrate response following radiation therapy for prostate cancer. J. Urol. 178, 2521–2525 (2007).
Elliott, S. et al. Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life. J. Sex. Med. 7, 2996–3010 (2010).
Kyrdalen, A. E., Dahl, A. A., Hernes, E., Hem, E. & Fosså, S. D. Fatigue in prostate cancer survivors treated with definitive radiotherapy and LHRH analogs. Prostate 70, 1480–1489 (2010).
Segal, R. J. et al. Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 21, 1653–1659 (2003).
Tyrrell, C. J. et al. Bicalutamide ('Casodex') 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme. Radiother. Oncol. 76, 4–10 (2005).
Tyrrell, C. J. et al. Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia. Int. J. Radiat. Oncol. Biol. Phys. 60, 476–483 (2004).
Arcangeli, G. et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 78, 11–18 (2010).
Arcangeli, G. et al. Acute and late toxicity in a randomized trial of conventional versus hypofractionated three-dimensional conformal radiotherapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 79, 1013–1021 (2011).
Yeoh, E. E. et al. Hypofractionated versus conventionally fractionated radiotherapy for prostate carcinoma: final results of phase III randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 81, 1271–1278 (2011).
Pollack, A. et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J. Clin. Oncol. 31, 3860–3868 (2013).
Dearnaley, D. et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial. Lancet Oncol. 13, 43–54 (2012).
Roach, M. 3rd et al. Predicting the risk of lymph node involvement using the pre-treatment prostate specific antigen and Gleason score in men with clinically localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 28, 33–37 (1994).
Roach, M. 3rd et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J. Clin. Oncol. 21, 1904–1911 (2003).
Lawton, C. A. 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. Int. J. Radiat. Oncol. Biol. Phys. 69, 646–655 (2007).
de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).
Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).
Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).
Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).
Nanda, A., Chen, M. H., Braccioforte, M. H., Moran, B. J. & D'Amico, A. V. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 302, 866–873 (2009).
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Mohiuddin, J., Baker, B. & Chen, R. Radiotherapy for high-risk prostate cancer. Nat Rev Urol 12, 145–154 (2015). https://doi.org/10.1038/nrurol.2015.25
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