The role of hormone therapy as a neoadjuvant to radical prostate radiotherapy.

Abstract

1. IntroductionNeoadjuvant hormone therapy may improve the therapeutic ratio of prostate radiotherapy in two ways: first, prostate shrinkage and the consequent reduction in target volume may reduce rectal toxicity, and so allow dose escalation; and second, hormone therapy may improve tumour control for a given radiation dose.1.1 Neoadjuvant Hormone Therapy may Reduce Radiation-induced Rectal ToxicityAndrogen deprivation reduces the volume of the prostate gland by 20–50% over a period of 3–6 months [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. The observed variation in prostate shrinkage between these studies may reflect differences in tumour volume, because androgen deprivation reduces prostate tumour volume to a greater extent than it does benign prostate tissue [4Padhani A MacVicar A Gapinski C et al.Effects of androgen deprivation of prostatic morphology and vascular permeability evaluated with MR imaging 1.Radiology. 2001; 218: 365-374Crossref PubMed Scopus (134) Google Scholar]. If the clinical target volume is based on the post-hormone prostate, then the rectal volume within the high-dose region is reduced [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. Given that there is a volume effect for late rectal toxicity [5Fiorino C Cozzarini C Vavassori V et al.Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.Radiother Oncol. 2002; 64: 1Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar], the use of neoadjuvant androgen deprivation is therefore expected to reduce the risk of rectal complications, and hence permit dose escalation. One proviso is that, if radiation treatment planning is performed early, within, say, the first 2 months of androgen deprivation, subsequent shrinking of the prostate before completion of radiotherapy may in fact increase the rectal volume irradiated [6Sanguineti G Marcenaro M Franzone P et al.Neoadjuvant androgen deprivation and prostate gland shrinkage duringconformal radiotherapy.Radiother Oncol. 2003; 66: 151-157Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar].In this issue of Clinical Oncology, Henderson et al. [12Henderson A Langley SEM Laing RW Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.Clin Oncol. 2003; 15: 318-321Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]report greater prostate shrinkage with neoadjuvant androgen deprivation than with anti-androgen monotherapy. Within the group of 74 men who had an initial prostate volume below 55 cm3and who received at least 3 months neoadjuvant hormone therapy, the mean volume reduction for androgen deprivation was 21% compared with 7% for anti-androgen monotherapy. The authors acknowledge that this reflects, in part, the disparity in initial prostate volume between the two groups, and so these figures over-estimate the magnitude of the difference attributable to the type of hormone therapy. Although the effect of the type of hormone therapy on prostate shrinkage remained statistically significant after controlling for initial prostate volume, the clinical significance of this finding is uncertain. Given that the efficacy of anti-androgen monotherapy is comparable to that of androgen deprivation in other settings [7Iversen P Tyrrell CJ Kaisary AV et al.Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow-up.J Urol. 2000; 164: 1579-1582Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar], it seems reasonable to offer anti-androgen monotherapy to men who wish to retain potency during neoadjuvant treatment. Indeed, there is some concern that androgen deprivation might increase mortality from causes other than prostate cancer [8Parker C Dearnaley D All-cause mortality in randomized trials of cancer screening [letter].J Natl Cancer Inst. 2002; 94 (author reply 865–866): 861-862Crossref PubMed Google Scholar], so it is conceivable that neoadjuvant anti-androgen monotherapy might not just be better tolerated than agonist treatment, but also improve overall survival. For men who choose neoadjuvant anti-androgen monotherapy, it is our policy to recommend continued treatment for 2 months after completing radiotherapy in order to mimic the delayed hormone recovery after neoadjuvant therapy with a luteinising hormone releasing hormone agonist [9Dearnaley D Norman A Shahidi M Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study.J Urol. 1999; 162: 170Abstract Full Text Full Text PDF PubMed Google Scholar].1.2 Neoadjuvant Hormone Therapy may Improve Tumour ControlIn RTOG trial 86-10, 470 men with bulky T2–T4 disease were randomised to radiotherapy to the prostate and pelvis either with or without 4 months of neoadjuvant maximal androgen blockade [10Pilepich M Winter K John M 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.Int J Radiat Oncol Biol Phys. 2001; 50: 1243-1252Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar]. With a median follow-up of 8.7 years, there was a trend towards improved overall survival for the group receiving neoadjuvant therapy (8-year survival: 53% vs 44%; P=0.10). A statistically significant survival advantage was seen in the subgroup of 129 cases with Gleason 2-6 disease, in whom 8-year overall survival was 70% for combined treatment vs 52% for radiation alone (P=0.015). RTOG trial 94-13 recruited over 1300 men with clinically-localised prostate cancer, a PSA of <100 ng/ml, and greater than 15% risk of lymph-node involvement, who all received radical radiotherapy and 4 months of maximal androgen blockade [11Roach M III Lu J Lawtron C et al.A phase III trial comparing whole-pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): preliminary analysis of RTOG 9413.Int J Radiat Oncol Biol Phys. 2001; 51: 3Abstract Full Text Full Text PDF Google Scholar]. A 2×2 randomisation was used to study the role of pelvic nodal irradiation and the timing of hormone therapy with respect to radiation. At a median follow-up of 5 years, there was a non-significant trend favouring neoadjuvant (starting 2 months before radiotherapy), rather than adjuvant (after completion of radiotherapy) hormone therapy, in terms of 5-year biochemical control (53% vs 48%, P=0.33). Interpretation of the results is complicated by the fact that there was an interaction between the two treatment randomisations. The benefit of neoadjuvant therapy seemed to be confined to patients receiving pelvic nodal irradiation. In these patients, 5-year biochemical control was 61% vs 49% for neoadjuvant and adjuvant hormone therapy, respectively (P=0.005). The timing of hormone therapy made no difference to the outcome of patients randomised to prostate only radiotherapy. One interpretation of these findings is that adequate treatment of the pelvic nodes is a significant determinant of outcome in these patients, and that the efficacy of nodal irradiation to 46 Gy is significantly improved by neoadjuvant androgen deprivation.2. ConclusionNeoadjuvant hormone therapy reduces the volume of the prostate, which, it is assumed, will reduce treatment-related rectal morbidity, but this assumption has not been formally tested. Neoadjuvant androgen deprivation also improves biochemical control after radical prostate radiotherapy, at least in men at significant risk of nodal involvement who receive treatment to the prostate and pelvis. This leaves a number of unanswered questions: what is the role of neoadjuvant androgen deprivation for lower risk disease, treated with radiotherapy to prostate alone? To what extent is the benefit of neoadjuvant therapy dependent on radiation dose and technique? What is the optimum timing and duration of neoadjuvant therapy? How does neoadjuvant anti-androgen monotherapy compare with androgen deprivation in terms of both tumour control and prostate shrinkage? Ongoing clinical trials are addressing some of these issues: EORTC 22991 is studying the role of 6 months of androgen deprivation started on day 1 of escalated dose-conformal radiotherapy to the prostate alone. RTOG 99-10 is comparing 4 months vs 8 months neoadjuvant androgen deprivation. There remains ample scope for future clinical trials to improve our knowledge of the appropriate use of neoadjuvant hormone therapy. 1. IntroductionNeoadjuvant hormone therapy may improve the therapeutic ratio of prostate radiotherapy in two ways: first, prostate shrinkage and the consequent reduction in target volume may reduce rectal toxicity, and so allow dose escalation; and second, hormone therapy may improve tumour control for a given radiation dose.1.1 Neoadjuvant Hormone Therapy may Reduce Radiation-induced Rectal ToxicityAndrogen deprivation reduces the volume of the prostate gland by 20–50% over a period of 3–6 months [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. The observed variation in prostate shrinkage between these studies may reflect differences in tumour volume, because androgen deprivation reduces prostate tumour volume to a greater extent than it does benign prostate tissue [4Padhani A MacVicar A Gapinski C et al.Effects of androgen deprivation of prostatic morphology and vascular permeability evaluated with MR imaging 1.Radiology. 2001; 218: 365-374Crossref PubMed Scopus (134) Google Scholar]. If the clinical target volume is based on the post-hormone prostate, then the rectal volume within the high-dose region is reduced [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. Given that there is a volume effect for late rectal toxicity [5Fiorino C Cozzarini C Vavassori V et al.Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.Radiother Oncol. 2002; 64: 1Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar], the use of neoadjuvant androgen deprivation is therefore expected to reduce the risk of rectal complications, and hence permit dose escalation. One proviso is that, if radiation treatment planning is performed early, within, say, the first 2 months of androgen deprivation, subsequent shrinking of the prostate before completion of radiotherapy may in fact increase the rectal volume irradiated [6Sanguineti G Marcenaro M Franzone P et al.Neoadjuvant androgen deprivation and prostate gland shrinkage duringconformal radiotherapy.Radiother Oncol. 2003; 66: 151-157Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar].In this issue of Clinical Oncology, Henderson et al. [12Henderson A Langley SEM Laing RW Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.Clin Oncol. 2003; 15: 318-321Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]report greater prostate shrinkage with neoadjuvant androgen deprivation than with anti-androgen monotherapy. Within the group of 74 men who had an initial prostate volume below 55 cm3and who received at least 3 months neoadjuvant hormone therapy, the mean volume reduction for androgen deprivation was 21% compared with 7% for anti-androgen monotherapy. The authors acknowledge that this reflects, in part, the disparity in initial prostate volume between the two groups, and so these figures over-estimate the magnitude of the difference attributable to the type of hormone therapy. Although the effect of the type of hormone therapy on prostate shrinkage remained statistically significant after controlling for initial prostate volume, the clinical significance of this finding is uncertain. Given that the efficacy of anti-androgen monotherapy is comparable to that of androgen deprivation in other settings [7Iversen P Tyrrell CJ Kaisary AV et al.Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow-up.J Urol. 2000; 164: 1579-1582Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar], it seems reasonable to offer anti-androgen monotherapy to men who wish to retain potency during neoadjuvant treatment. Indeed, there is some concern that androgen deprivation might increase mortality from causes other than prostate cancer [8Parker C Dearnaley D All-cause mortality in randomized trials of cancer screening [letter].J Natl Cancer Inst. 2002; 94 (author reply 865–866): 861-862Crossref PubMed Google Scholar], so it is conceivable that neoadjuvant anti-androgen monotherapy might not just be better tolerated than agonist treatment, but also improve overall survival. For men who choose neoadjuvant anti-androgen monotherapy, it is our policy to recommend continued treatment for 2 months after completing radiotherapy in order to mimic the delayed hormone recovery after neoadjuvant therapy with a luteinising hormone releasing hormone agonist [9Dearnaley D Norman A Shahidi M Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study.J Urol. 1999; 162: 170Abstract Full Text Full Text PDF PubMed Google Scholar].1.2 Neoadjuvant Hormone Therapy may Improve Tumour ControlIn RTOG trial 86-10, 470 men with bulky T2–T4 disease were randomised to radiotherapy to the prostate and pelvis either with or without 4 months of neoadjuvant maximal androgen blockade [10Pilepich M Winter K John M 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.Int J Radiat Oncol Biol Phys. 2001; 50: 1243-1252Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar]. With a median follow-up of 8.7 years, there was a trend towards improved overall survival for the group receiving neoadjuvant therapy (8-year survival: 53% vs 44%; P=0.10). A statistically significant survival advantage was seen in the subgroup of 129 cases with Gleason 2-6 disease, in whom 8-year overall survival was 70% for combined treatment vs 52% for radiation alone (P=0.015). RTOG trial 94-13 recruited over 1300 men with clinically-localised prostate cancer, a PSA of <100 ng/ml, and greater than 15% risk of lymph-node involvement, who all received radical radiotherapy and 4 months of maximal androgen blockade [11Roach M III Lu J Lawtron C et al.A phase III trial comparing whole-pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): preliminary analysis of RTOG 9413.Int J Radiat Oncol Biol Phys. 2001; 51: 3Abstract Full Text Full Text PDF Google Scholar]. A 2×2 randomisation was used to study the role of pelvic nodal irradiation and the timing of hormone therapy with respect to radiation. At a median follow-up of 5 years, there was a non-significant trend favouring neoadjuvant (starting 2 months before radiotherapy), rather than adjuvant (after completion of radiotherapy) hormone therapy, in terms of 5-year biochemical control (53% vs 48%, P=0.33). Interpretation of the results is complicated by the fact that there was an interaction between the two treatment randomisations. The benefit of neoadjuvant therapy seemed to be confined to patients receiving pelvic nodal irradiation. In these patients, 5-year biochemical control was 61% vs 49% for neoadjuvant and adjuvant hormone therapy, respectively (P=0.005). The timing of hormone therapy made no difference to the outcome of patients randomised to prostate only radiotherapy. One interpretation of these findings is that adequate treatment of the pelvic nodes is a significant determinant of outcome in these patients, and that the efficacy of nodal irradiation to 46 Gy is significantly improved by neoadjuvant androgen deprivation. Neoadjuvant hormone therapy may improve the therapeutic ratio of prostate radiotherapy in two ways: first, prostate shrinkage and the consequent reduction in target volume may reduce rectal toxicity, and so allow dose escalation; and second, hormone therapy may improve tumour control for a given radiation dose. 1.1 Neoadjuvant Hormone Therapy may Reduce Radiation-induced Rectal ToxicityAndrogen deprivation reduces the volume of the prostate gland by 20–50% over a period of 3–6 months [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. The observed variation in prostate shrinkage between these studies may reflect differences in tumour volume, because androgen deprivation reduces prostate tumour volume to a greater extent than it does benign prostate tissue [4Padhani A MacVicar A Gapinski C et al.Effects of androgen deprivation of prostatic morphology and vascular permeability evaluated with MR imaging 1.Radiology. 2001; 218: 365-374Crossref PubMed Scopus (134) Google Scholar]. If the clinical target volume is based on the post-hormone prostate, then the rectal volume within the high-dose region is reduced [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. Given that there is a volume effect for late rectal toxicity [5Fiorino C Cozzarini C Vavassori V et al.Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.Radiother Oncol. 2002; 64: 1Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar], the use of neoadjuvant androgen deprivation is therefore expected to reduce the risk of rectal complications, and hence permit dose escalation. One proviso is that, if radiation treatment planning is performed early, within, say, the first 2 months of androgen deprivation, subsequent shrinking of the prostate before completion of radiotherapy may in fact increase the rectal volume irradiated [6Sanguineti G Marcenaro M Franzone P et al.Neoadjuvant androgen deprivation and prostate gland shrinkage duringconformal radiotherapy.Radiother Oncol. 2003; 66: 151-157Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar].In this issue of Clinical Oncology, Henderson et al. [12Henderson A Langley SEM Laing RW Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.Clin Oncol. 2003; 15: 318-321Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]report greater prostate shrinkage with neoadjuvant androgen deprivation than with anti-androgen monotherapy. Within the group of 74 men who had an initial prostate volume below 55 cm3and who received at least 3 months neoadjuvant hormone therapy, the mean volume reduction for androgen deprivation was 21% compared with 7% for anti-androgen monotherapy. The authors acknowledge that this reflects, in part, the disparity in initial prostate volume between the two groups, and so these figures over-estimate the magnitude of the difference attributable to the type of hormone therapy. Although the effect of the type of hormone therapy on prostate shrinkage remained statistically significant after controlling for initial prostate volume, the clinical significance of this finding is uncertain. Given that the efficacy of anti-androgen monotherapy is comparable to that of androgen deprivation in other settings [7Iversen P Tyrrell CJ Kaisary AV et al.Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow-up.J Urol. 2000; 164: 1579-1582Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar], it seems reasonable to offer anti-androgen monotherapy to men who wish to retain potency during neoadjuvant treatment. Indeed, there is some concern that androgen deprivation might increase mortality from causes other than prostate cancer [8Parker C Dearnaley D All-cause mortality in randomized trials of cancer screening [letter].J Natl Cancer Inst. 2002; 94 (author reply 865–866): 861-862Crossref PubMed Google Scholar], so it is conceivable that neoadjuvant anti-androgen monotherapy might not just be better tolerated than agonist treatment, but also improve overall survival. For men who choose neoadjuvant anti-androgen monotherapy, it is our policy to recommend continued treatment for 2 months after completing radiotherapy in order to mimic the delayed hormone recovery after neoadjuvant therapy with a luteinising hormone releasing hormone agonist [9Dearnaley D Norman A Shahidi M Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study.J Urol. 1999; 162: 170Abstract Full Text Full Text PDF PubMed Google Scholar]. Androgen deprivation reduces the volume of the prostate gland by 20–50% over a period of 3–6 months [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. The observed variation in prostate shrinkage between these studies may reflect differences in tumour volume, because androgen deprivation reduces prostate tumour volume to a greater extent than it does benign prostate tissue [4Padhani A MacVicar A Gapinski C et al.Effects of androgen deprivation of prostatic morphology and vascular permeability evaluated with MR imaging 1.Radiology. 2001; 218: 365-374Crossref PubMed Scopus (134) Google Scholar]. If the clinical target volume is based on the post-hormone prostate, then the rectal volume within the high-dose region is reduced [1Shearer RJ Davies JH Gelister JSK et al.Hormonal cytoreduction and radiotherapy for carcinoma of the prostate.Br J Urol. 1992; 69: 521-524Crossref PubMed Scopus (72) Google Scholar, 2Zelefsky MJ Leibel SA Burman CM et al.Neoadjuvanthormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy.Int J Radiat Oncol Biol Phys. 1994; 29: 755-761Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 3Forman JD Kumar R Haas G et al.Neoadjuvant hormonal downsizing of localised carcinoma of the prostate: effects on the volume of normal tissue radiation.Cancer Invest. 1995; 13: 8-15Crossref PubMed Scopus (85) Google Scholar]. Given that there is a volume effect for late rectal toxicity [5Fiorino C Cozzarini C Vavassori V et al.Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.Radiother Oncol. 2002; 64: 1Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar], the use of neoadjuvant androgen deprivation is therefore expected to reduce the risk of rectal complications, and hence permit dose escalation. One proviso is that, if radiation treatment planning is performed early, within, say, the first 2 months of androgen deprivation, subsequent shrinking of the prostate before completion of radiotherapy may in fact increase the rectal volume irradiated [6Sanguineti G Marcenaro M Franzone P et al.Neoadjuvant androgen deprivation and prostate gland shrinkage duringconformal radiotherapy.Radiother Oncol. 2003; 66: 151-157Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. In this issue of Clinical Oncology, Henderson et al. [12Henderson A Langley SEM Laing RW Is bicalutamide equivalent to goserelin for prostate volume reduction before radiation therapy? A prospective, observational study.Clin Oncol. 2003; 15: 318-321Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]report greater prostate shrinkage with neoadjuvant androgen deprivation than with anti-androgen monotherapy. Within the group of 74 men who had an initial prostate volume below 55 cm3and who received at least 3 months neoadjuvant hormone therapy, the mean volume reduction for androgen deprivation was 21% compared with 7% for anti-androgen monotherapy. The authors acknowledge that this reflects, in part, the disparity in initial prostate volume between the two groups, and so these figures over-estimate the magnitude of the difference attributable to the type of hormone therapy. Although the effect of the type of hormone therapy on prostate shrinkage remained statistically significant after controlling for initial prostate volume, the clinical significance of this finding is uncertain. Given that the efficacy of anti-androgen monotherapy is comparable to that of androgen deprivation in other settings [7Iversen P Tyrrell CJ Kaisary AV et al.Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow-up.J Urol. 2000; 164: 1579-1582Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar], it seems reasonable to offer anti-androgen monotherapy to men who wish to retain potency during neoadjuvant treatment. Indeed, there is some concern that androgen deprivation might increase mortality from causes other than prostate cancer [8Parker C Dearnaley D All-cause mortality in randomized trials of cancer screening [letter].J Natl Cancer Inst. 2002; 94 (author reply 865–866): 861-862Crossref PubMed Google Scholar], so it is conceivable that neoadjuvant anti-androgen monotherapy might not just be better tolerated than agonist treatment, but also improve overall survival. For men who choose neoadjuvant anti-androgen monotherapy, it is our policy to recommend continued treatment for 2 months after completing radiotherapy in order to mimic the delayed hormone recovery after neoadjuvant therapy with a luteinising hormone releasing hormone agonist [9Dearnaley D Norman A Shahidi M Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study.J Urol. 1999; 162: 170Abstract Full Text Full Text PDF PubMed Google Scholar]. 1.2 Neoadjuvant Hormone Therapy may Improve Tumour ControlIn RTOG trial 86-10, 470 men with bulky T2–T4 disease were randomised to radiotherapy to the prostate and pelvis either with or without 4 months of neoadjuvant maximal androgen blockade [10Pilepich M Winter K John M 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.Int J Radiat Oncol Biol Phys. 2001; 50: 1243-1252Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar]. With a median follow-up of 8.7 years, there was a trend towards improved overall survival for the group receiving neoadjuvant therapy (8-year survival: 53% vs 44%; P=0.10). A statistically significant survival advantage was seen in the subgroup of 129 cases with Gleason 2-6 disease, in whom 8-year overall survival was 70% for combined treatment vs 52% for radiation alone (P=0.015). RTOG trial 94-13 recruited over 1300 men with clinically-localised prostate cancer, a PSA of <100 ng/ml, and greater than 15% risk of lymph-node involvement, who all received radical radiotherapy and 4 months of maximal androgen blockade [11Roach M III Lu J Lawtron C et al.A phase III trial comparing whole-pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): preliminary analysis of RTOG 9413.Int J Radiat Oncol Biol Phys. 2001; 51: 3Abstract Full Text Full Text PDF Google Scholar]. A 2×2 randomisation was used to study the role of pelvic nodal irradiation and the timing of hormone therapy with respect to radiation. At a median follow-up of 5 years, there was a non-significant trend favouring neoadjuvant (starting 2 months before radiotherapy), rather than adjuvant (after completion of radiotherapy) hormone therapy, in terms of 5-year biochemical control (53% vs 48%, P=0.33). Interpretation of the results is complicated by the fact that there was an interaction between the two treatment randomisations. The benefit of neoadjuvant therapy seemed to be confined to patients receiving pelvic nodal irradiation. In these patients, 5-year biochemical control was 61% vs 49% for neoadjuvant and adjuvant hormone therapy, respectively (P=0.005). The timing of hormone therapy made no difference to the outcome of patients randomised to prostate only radiotherapy. One interpretation of these findings is that adequate treatment of the pelvic nodes is a significant determinant of outcome in these patients, and that the efficacy of nodal irradiation to 46 Gy is significantly improved by neoadjuvant androgen deprivation. In RTOG trial 86-10, 470 men with bulky T2–T4 disease were randomised to radiotherapy to the prostate and pelvis either with or without 4 months of neoadjuvant maximal androgen blockade [10Pilepich M Winter K John M 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.Int J Radiat Oncol Biol Phys. 2001; 50: 1243-1252Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar]. With a median follow-up of 8.7 years, there was a trend towards improved overall survival for the group receiving neoadjuvant therapy (8-year survival: 53% vs 44%; P=0.10). A statistically significant survival advantage was seen in the subgroup of 129 cases with Gleason 2-6 disease, in whom 8-year overall survival was 70% for combined treatment vs 52% for radiation alone (P=0.015). RTOG trial 94-13 recruited over 1300 men with clinically-localised prostate cancer, a PSA of <100 ng/ml, and greater than 15% risk of lymph-node involvement, who all received radical radiotherapy and 4 months of maximal androgen blockade [11Roach M III Lu J Lawtron C et al.A phase III trial comparing whole-pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): preliminary analysis of RTOG 9413.Int J Radiat Oncol Biol Phys. 2001; 51: 3Abstract Full Text Full Text PDF Google Scholar]. A 2×2 randomisation was used to study the role of pelvic nodal irradiation and the timing of hormone therapy with respect to radiation. At a median follow-up of 5 years, there was a non-significant trend favouring neoadjuvant (starting 2 months before radiotherapy), rather than adjuvant (after completion of radiotherapy) hormone therapy, in terms of 5-year biochemical control (53% vs 48%, P=0.33). Interpretation of the results is complicated by the fact that there was an interaction between the two treatment randomisations. The benefit of neoadjuvant therapy seemed to be confined to patients receiving pelvic nodal irradiation. In these patients, 5-year biochemical control was 61% vs 49% for neoadjuvant and adjuvant hormone therapy, respectively (P=0.005). The timing of hormone therapy made no difference to the outcome of patients randomised to prostate only radiotherapy. One interpretation of these findings is that adequate treatment of the pelvic nodes is a significant determinant of outcome in these patients, and that the efficacy of nodal irradiation to 46 Gy is significantly improved by neoadjuvant androgen deprivation. 2. ConclusionNeoadjuvant hormone therapy reduces the volume of the prostate, which, it is assumed, will reduce treatment-related rectal morbidity, but this assumption has not been formally tested. Neoadjuvant androgen deprivation also improves biochemical control after radical prostate radiotherapy, at least in men at significant risk of nodal involvement who receive treatment to the prostate and pelvis. This leaves a number of unanswered questions: what is the role of neoadjuvant androgen deprivation for lower risk disease, treated with radiotherapy to prostate alone? To what extent is the benefit of neoadjuvant therapy dependent on radiation dose and technique? What is the optimum timing and duration of neoadjuvant therapy? How does neoadjuvant anti-androgen monotherapy compare with androgen deprivation in terms of both tumour control and prostate shrinkage? Ongoing clinical trials are addressing some of these issues: EORTC 22991 is studying the role of 6 months of androgen deprivation started on day 1 of escalated dose-conformal radiotherapy to the prostate alone. RTOG 99-10 is comparing 4 months vs 8 months neoadjuvant androgen deprivation. There remains ample scope for future clinical trials to improve our knowledge of the appropriate use of neoadjuvant hormone therapy. Neoadjuvant hormone therapy reduces the volume of the prostate, which, it is assumed, will reduce treatment-related rectal morbidity, but this assumption has not been formally tested. Neoadjuvant androgen deprivation also improves biochemical control after radical prostate radiotherapy, at least in men at significant risk of nodal involvement who receive treatment to the prostate and pelvis. This leaves a number of unanswered questions: what is the role of neoadjuvant androgen deprivation for lower risk disease, treated with radiotherapy to prostate alone? To what extent is the benefit of neoadjuvant therapy dependent on radiation dose and technique? What is the optimum timing and duration of neoadjuvant therapy? How does neoadjuvant anti-androgen monotherapy compare with androgen deprivation in terms of both tumour control and prostate shrinkage? Ongoing clinical trials are addressing some of these issues: EORTC 22991 is studying the role of 6 months of androgen deprivation started on day 1 of escalated dose-conformal radiotherapy to the prostate alone. RTOG 99-10 is comparing 4 months vs 8 months neoadjuvant androgen deprivation. There remains ample scope for future clinical trials to improve our knowledge of the appropriate use of neoadjuvant hormone therapy.