- Email: [email protected]
Who Benefits from Neoadjuvant or Adjuvant Hormone Therapy?
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Who Benefits from Neoadjuvant or Adjuvant Hormone Therapy? Alberto Bossi * Institut Gustave Roussy, Department of Radiotherapy, 39, rue Camille Desmoulins, 94805 Villejuif, France
Article info
Abstract
Keywords: Adjuvant therapy Androgen-deprivation therapy Hormone therapy Neoadjuvant therapy Prostate cancer Radical prostatectomy Radiotherapy
Context: Although there is an increasing interest in the use of neoadjuvant or adjuvant hormone therapy (HT) combined with curative treatment for patients with prostate cancer (PCa), the issue of who may benefit from such therapy is still open. Objective: To summarise the current status of neoadjuvant and adjuvant HT as a curative treatment for patients with PCa. Evidence acquisition: This manuscript is based on a presentation given at a satellite symposium on PCa held at the 2009 European Association of Urology (EAU) Congress in Stockholm, Sweden. Data were retrieved from recent original articles, review papers, and abstracts on neoadjuvant or adjuvant HT to local treatment for PCa. Evidence synthesis: Neoadjuvant HT to radical prostatectomy does not offer a survival benefit over surgery alone in patients with localised and locally advanced PCa. Neoadjuvant HT to radiation therapy (RT) appears to improve treatment outcomes, except overall survival (OS), over RT alone in patients with locally advanced PCa, without increasing the risk of fatal cardiac events. Several large, randomised phase 3 studies have shown that adjuvant HT with RT increases OS compared with RT alone in patients with high-risk localised or locally advanced PCa. However, the added value of HT to RT seems to pertain only to men with no or minimal comorbidity. With regard to the optimal duration, long-term adjuvant HT appears superior over short-term adjuvant HT with RT, especially in patients with poor-risk PCa. Conclusions: Neoadjuvant or adjuvant HT to RT may improve treatment outcomes, including OS in appropriately selected patients with PCa.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Tel. +33 (0) 1 42114125; Fax: +33 (0) 1 42115281. E-mail address: [email protected] (A. Bossi).
1.
Introduction
Over the past decade, there has been increasing concern that local treatment with radical prostatectomy (RP) or radiation therapy (RT) alone is often not sufficient to eradicate localised prostate cancer (PCa). It is still questioned whether additional hormone therapy (HT) in either a neoadjuvant or adjuvant setting may improve treatment outcomes (eg, distant metastases, local failure, and overall
survival [OS]) in these patients. According to the European Association of Urology (EAU) guidelines, a combination of HT with RT should be recommended in patients with locally advanced T3–4 N0 M0 PCa, as the addition of HT to RT can offer a survival benefit over RT alone [1]. Neoadjuvant HT to RT is currently used to shrink the prostate, therefore enabling optimal radiation doses to the prostate and reducing exposure of surrounding tissue. HT added to RT can also reduce the risk of distant metastases. However, HT
1569-9056/$ – see front matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2009.09.003
849
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
has been associated with substantial adverse events such as hot flushes, metabolic syndrome, loss of libido, and erectile dysfunction (ED) [1]. As many PCa patients are still young and physically and sexually active, it is of paramount importance to appropriately select patients who may benefit from additional HT. In addition, further research is needed to determine the optimal duration of HT. This paper reviews the current status of neoadjuvant or adjuvant HT to curative treatment for patients with PCa. 2.
Evidence acquisition
This paper is based on a presentation given at a satellite symposium on PCa that was held during the 2009 EAU Congress on 18 March 2009 in Stockholm, Sweden. Data were retrieved from recent original articles, review articles, and abstracts on neoadjuvant or adjuvant HT to local treatment for PCa.
3.
Evidence synthesis
3.1.
What is the benefit of neoadjuvant hormone therapy to
radical prostatectomy?
According to a systematic review and meta-analysis of randomised trials of neoadjuvant HT in localised and locally advanced PCa, neoadjuvant HT to RP did not provide a statistically significant survival benefit over surgery alone (pooled relative risk: 1.00; 95% confidence interval [CI], 0.97–1.04; p = 0.95; Table 1) [2]. Moreover, Stephenson et al [3] developed a nomogram, with a concordance index of 0.8, to predict the long-term risk of PCa-specific mortality based on clinical data of 6398 patients who underwent RP from 1987 to 2005 in two US tertiary referral centres. External
validation was performed on 4103 patients from a separate institution. Fifteen-year PCa-specific mortality and allcause mortality were 12% and 38%, respectively. Surprisingly, besides biopsy Gleason grade, prostate-specific antigen (PSA), and year of surgery, neoadjuvant androgen-deprivation therapy (ADT) seems to be statistically significantly associated with PCa-specific mortality. 3.2.
What is the benefit of neoadjuvant and adjuvant hormone
therapy to radiation therapy?
HT is frequently combined with RT. Already >10 yr ago, Zietman et al [4], using an androgen-dependent breast cancer line (Shionogi tumour model), reported a significant reduction in the radiation dose required to control 50% of tumours when RT was combined with HT compared with RT alone. In addition, neoadjuvant HT resulted in a better efficacy than adjuvant HT to RT. With regard to clinical studies, the Radiation Therapy Oncology Group (RTOG) protocol 8610 was the first randomised phase 3 trial evaluating the effect of neoadjuvant HT to RT in 456 men with bulky (5 5 cm) T2-4 N0-X M0 tumours between 1987 and 1991 [5]. At a follow-up period of 10 yr, patients who received 2 mo of neoadjuvant ADT plus 2 mo of concurrent ADT combined with RT demonstrated statistically significantly fewer clinical failures ( p < 0.0001), distant metastases ( p = 0.006), and PCa-specific deaths ( p = 0.01) than patients who were treated with RT alone (Table 1) [5]. Although the 10-yr OS was 9% higher among men treated with neoadjuvant HT to RT versus RT alone, the improvement was not statistically significant. No differences in the risk of fatal cardiac events were observed between the treatment groups. Furthermore, several randomised phase 3 clinical trials investigated the value of adjuvant HT to RT in patients with high-risk localised or locally advanced PCa [6–9]. Bolla et al
Table 1 – Overview of randomised, controlled, phase 3 trials evaluating neoadjuvant or adjuvant hormone therapy to radical prostatectomy or radiation therapy for the treatment of prostate cancer Trial
Study population
Treatment
Result
Cochrane meta-analysis [2] RTOG 8610 [5]
Localised/locally advanced PCa T2–4 N0–X M0
Neoadjuvant HT to RP vs RP alone
No statistically significant improvement in OS
2 mo of neoadjuvant HT plus 2 mo of concurrent HT to RT vs RT alone
EORTC 22861 [10]
T1–T2 grade 3 or T3–T4 N0–1 M0 High-risk localised or locally advanced Localised T1c–2b N1–2 or pN1-2 or T2c–4 N0–2 M0 Locally advanced
Long-term (3 yr) adjuvant HT to RT vs RT alone HT + RT vs HT alone
Statistically significantly fewer 10-yr clinical failures, distant metastases, and PCa-specific deaths Better 10-yr OS but not statistically significant Significantly better 10-yr OS
SPCG-7/SFUO-3 [11] Canadian trial [14] EORTC 22961 [15]
RTOG 9202 [16]
Significantly lower 10-yr PCa-specific mortality
8-mo vs 3-mo neoadjuvant HT to RT 3-yr vs 6-mo adjuvant HT to RT
No increased 5-yr DFS, except in high-risk patients Better 5-yr OS
28-mo vs 4-mo HT to RT
Statistically significantly improved 10-yr DFS, DSS, local progression, distant metastasis, and biochemical failure No improved 10-yr OS, except in a subset of patients with Gleason score 8–10
PCa = prostate cancer; HT = hormone therapy; RP = radical prostatectomy; OS = overall survival; RTOG = Radiation Therapy Oncology Group; RT = radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; SPCG-7/SFUO-3 = Scandinavian Prostate Cancer Group Study 7 and Swedish Association for Urological Oncology 3; DFS = disease-free survival; DSS = disease-specific survival.
850
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
to apply only to men with no or minimal comorbidities. Among men with moderate or severe comorbidities, OS rates did not differ significantly ( p = 0.08). 3.3.
What is the optimal duration of neoadjuvant and adjuvant
hormone therapy to radiation therapy?
Fig. 1 – Ten-year results of the European Organisation for Research and Treatment of Cancer 22861 trial comparing long-term adjuvant hormone therapy plus radiation therapy (RT) with RT alone in patients with locally advanced prostate cancer [10]. OS = overall survival; RT = radiation therapy; HT = hormone therapy.
[7] demonstrated that HT starting on the first day of RT and continued for 3 yr was associated with a significantly better 5-yr OS than RT alone (78% vs 62%, p = 0.0002) in patients with T1-T2 grade 3 or T3-T4 N0-1 M0 PCa enrolled in the European Organisation for Research and Treatment of Cancer (EORTC) study 22861 between 1987 and 1995. Even at a longer follow-up period, the OS benefit was maintained in patients receiving long-term adjuvant HT (3 yr) to RT for locally advanced PCa without increasing cardiovascular toxicity (Fig. 1 and Table 1) [10]. It is still not proven whether the benefits are the result of hormoneinduced radiosensitisation or of an effect on micrometastases. Recently, Widmark et al [11] performed an open, randomised phase 3 study comparing HT with and without RT to assess the effect of RT. The Scandinavian Prostate Cancer Group Study 7 and the Swedish Association for Urological Oncology 3 (SPCG-7/SFUO-3) trial included 875 men from 47 centres in Norway, Sweden, and Denmark who were treated with life-long antiandrogen therapy alone or antiandrogens plus RT for high-risk localised or locally advanced PCa. Median follow-up was 7.6 yr. The cumulative incidence at 10 yr for PCa-specific mortality was significantly lower for patients who were treated with antiandrogens plus RT than for patients who received antiandrogen therapy alone (11.9% vs 23.9%, p < 0.001; Table 1). This significant difference also translated into improved OS. After 5 yr, urgency, urinary incontinence, and ED were slightly more frequent among patients who received antiandrogens plus RT. However, at a follow-up period of 4 yr, quality of life was comparable between the treatment groups. Although the addition of HT to RT may prolong diseasespecific survival (DSS) and even OS in patients with highrisk localised or locally advanced PCa, there is some evidence suggesting that HT is associated with an increased risk of cardiovascular events [12]. D’Amico et al [13] examined the impact of comorbidities on treatment outcome in 206 men who received RT alone or RT plus 6 mo of HT for localised but unfavourable-risk PCa. At a median follow-up of 7.6 yr, 36% of patients died. The OS was significantly increased in men randomised to RT and HT compared with RT alone ( p = 0.01), but this result appeared
Because the optimal duration of neoadjuvant or adjuvant HT has not yet been defined, several randomised trials have been performed to compare different durations of HT. In addition, shortening the period of HT may reduce the therapy’s costs and adverse events. This is the rationale for a Canadian multicentre, randomised, controlled phase 3 trial that evaluated the effect of 3 mo versus 8 mo of neoadjuvant ADT to RT in 378 men with clinically localised PCa between 1995 and 2001 [14]. A longer period of neoadjuvant HT to RT did not improve the 5-yr disease-free survival (DFS), except in a subgroup of high-risk patients (Fig. 2 and Table 1). In the EORTC randomised phase 3 trial 22961, Bolla et al [15] compared 6 mo with 3 yr of concomitant and adjuvant HT to RT in 970 patients with T1c-2b N1-2 or pN1-2 or with T2c-4 N0-2 M0 PCa. Noninferior OS was defined as a mortality hazard ratio (HR) 1.35 for short-term HT versus long-term HT. At a median follow-up of 6.4 yr, 24% of patients died. The 5-yr OS rate was 81.1% versus 85.1% (HR: 1.47; 95% CI, 1.12– 1.94) for patients who received 6 mo of HT compared with 3 yr of HT, respectively. Thus, noninferiority in terms of OS could not be proven in patients receiving 6 mo versus 3 yr of adjuvant HT to RT (Table 1). In addition, at 5 yr, clinical progression-free survival (PFS) and biochemical PFS were significantly worse for patients who were treated with 6mo adjuvant HT than patients randomised to 3-yr adjuvant HT to RT. In accordance with EORTC trial 22961, updated RTOG study 9202 reported that the addition of long-term HT (24 mo) improved outcomes in patients with locally advanced PCa who were treated with short-term HT (4 mo) before and during RT (n = 758) compared with no further HT (n = 763) in terms of 10-yr DFS (22.5% vs 13.2%; p < 0.0001), DSS (88.7% vs 83.9%; p = 0.0042), local progression (12.3% vs 22.2%; p < 0.0001), distant metastasis (14.8% vs 22.8%; p < 0.0001), and biochemical failure (51.9% vs 68.1%; p 0.0001; Table 1) [16]. A difference in OS at 10 yr was not
Fig. 2 – The effect of 3 mo versus 8 mo of neoadjuvant hormone therapy to radiation therapy in patients with clinically localised prostate cancer enrolled in a Canadian multicentre, randomised, controlled phase 3 trial [14]. HT = hormone therapy; RT = radiation therapy; DFS = disease-free survival.
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
observed, except in a subset of patients with Gleason score 8–10 (45.1% vs 31.9%; p = 0.0061) in favour of longterm HT to RT.
851
[3] Stephenson A, Kattan MW, Eastham JA, et al. Prostate cancerspecific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era [abstract 1889]. J Urol 2008; 179:649. [4] Zietman AL, Prince EA, Nakfoor BM, Park JJ. Androgen deprivation
4.
Conclusions
and radiation therapy: sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 1997;38:1067–70.
Neoadjuvant HT to RP does not seem to offer a survival benefit over RP alone in patients with localised or locally advanced PCa. Moreover, besides biopsy Gleason grade, PSA, and year of surgery, neoadjuvant HT before surgery may have a detrimental effect on PCa-specific survival. In contrast, neoadjuvant HT to RT appears to improve treatment outcomes, except OS, over RT alone in patients with locally advanced PCa. Adjuvant HT to RT can significantly improve OS compared with RT alone in high-risk localised and locally advanced PCa patients. Furthermore, compared with HT alone, the addition of RT to HT halved the 10-yr PCa-specific mortality in patients with high-risk localised or locally advanced PCa, with acceptable risk of adverse events. However, the OS benefit may pertain only to patients with no or minimal comorbidities. With regard to the optimal duration of neoadjuvant or adjuvant HT to RT, the EORTC 22961 trial failed to prove noninferiority in terms of OS of 6 mo of HT compared with 3 yr of HT to RT. In line with these data, it has been suggested that long-term HT should be the standard of care, especially in patients with high-risk PCa.
[5] Roach III M, Bae K, Speight J, 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 2008;26:585–91. [6] Pilepich MV, Winter K, Lawton C, et al. Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31 [abstract 1530]. Proc Am Soc Clin Oncol 2003;22:381. [7] Bolla M, Collette L, Blank L, 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 2002;360:103–8. [8] Hanks GE, Pajak TF, Porter A, 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 2003;21:3972–8. [9] Roach M, DeSilvio M, Lawton C, 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 2003;21:1904–11. [10] Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy:
Conflicts of interest
a phase III EORTC study [abstract 65]. Int J Radiat Oncol Biol Phys 2008;72:S30–1.
The author has no conflicts of interest.
[11] Widmark A, Klepp O, Solberg 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 2009;373:301–8.
Funding support
[12] Isbarn H, Boccon-Gibod L, Caroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits
The publication of this review was supported by Astellas Pharma Europe Ltd.
and risks. Eur Urol 2009;55:62–75. [13] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008;299:289–95.
Acknowledgements
[14] Crook J, Ludgate C, Malone S, et al. Final report of multicenter Canadian phase III randomized trial of 3 versus 8 months of
The author is grateful to Ismar Healthcare NV for assistance with writing the manuscript.
neoadjuvant androgen deprivation therapy before conventionaldose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;73:327–33. [15] Bolla M, De Reijke ThM, Van Tienhoven GJ, et al. Six-month con-
References
comitant and adjuvant hormonal treatment with external beam irradiation is inferior to 3-years hormonal treatment for locally
[1] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53:68–80.
advanced prostate cancer: results of the EORTC randomised phase III trial 22961 [abstract 186]. Eur Urol Suppl 2008;7:117.
[2] Shelley MD, Kumar S, Wilt T, et al. A systematic review and meta-
[16] Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation
analysis of randomised trials of neo-adjuvant hormone therapy for
therapy oncology group protocol 92-02: a phase III trial of the
localised and locally advanced prostate carcinoma. Cancer Treat
duration of elective androgen deprivation in locally advanced
Rev 2009;35:9–17.
prostate cancer. J Clin Oncol 2008;26:2497–504.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Who Benefits from Neoadjuvant or Adjuvant Hormone Therapy? Alberto Bossi * Institut Gustave Roussy, Department of Radiotherapy, 39, rue Camille Desmoulins, 94805 Villejuif, France
Article info
Abstract
Keywords: Adjuvant therapy Androgen-deprivation therapy Hormone therapy Neoadjuvant therapy Prostate cancer Radical prostatectomy Radiotherapy
Context: Although there is an increasing interest in the use of neoadjuvant or adjuvant hormone therapy (HT) combined with curative treatment for patients with prostate cancer (PCa), the issue of who may benefit from such therapy is still open. Objective: To summarise the current status of neoadjuvant and adjuvant HT as a curative treatment for patients with PCa. Evidence acquisition: This manuscript is based on a presentation given at a satellite symposium on PCa held at the 2009 European Association of Urology (EAU) Congress in Stockholm, Sweden. Data were retrieved from recent original articles, review papers, and abstracts on neoadjuvant or adjuvant HT to local treatment for PCa. Evidence synthesis: Neoadjuvant HT to radical prostatectomy does not offer a survival benefit over surgery alone in patients with localised and locally advanced PCa. Neoadjuvant HT to radiation therapy (RT) appears to improve treatment outcomes, except overall survival (OS), over RT alone in patients with locally advanced PCa, without increasing the risk of fatal cardiac events. Several large, randomised phase 3 studies have shown that adjuvant HT with RT increases OS compared with RT alone in patients with high-risk localised or locally advanced PCa. However, the added value of HT to RT seems to pertain only to men with no or minimal comorbidity. With regard to the optimal duration, long-term adjuvant HT appears superior over short-term adjuvant HT with RT, especially in patients with poor-risk PCa. Conclusions: Neoadjuvant or adjuvant HT to RT may improve treatment outcomes, including OS in appropriately selected patients with PCa.
Please visit www.eu-acme.org/ europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
# 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Tel. +33 (0) 1 42114125; Fax: +33 (0) 1 42115281. E-mail address: [email protected] (A. Bossi).
1.
Introduction
Over the past decade, there has been increasing concern that local treatment with radical prostatectomy (RP) or radiation therapy (RT) alone is often not sufficient to eradicate localised prostate cancer (PCa). It is still questioned whether additional hormone therapy (HT) in either a neoadjuvant or adjuvant setting may improve treatment outcomes (eg, distant metastases, local failure, and overall
survival [OS]) in these patients. According to the European Association of Urology (EAU) guidelines, a combination of HT with RT should be recommended in patients with locally advanced T3–4 N0 M0 PCa, as the addition of HT to RT can offer a survival benefit over RT alone [1]. Neoadjuvant HT to RT is currently used to shrink the prostate, therefore enabling optimal radiation doses to the prostate and reducing exposure of surrounding tissue. HT added to RT can also reduce the risk of distant metastases. However, HT
1569-9056/$ – see front matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2009.09.003
849
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
has been associated with substantial adverse events such as hot flushes, metabolic syndrome, loss of libido, and erectile dysfunction (ED) [1]. As many PCa patients are still young and physically and sexually active, it is of paramount importance to appropriately select patients who may benefit from additional HT. In addition, further research is needed to determine the optimal duration of HT. This paper reviews the current status of neoadjuvant or adjuvant HT to curative treatment for patients with PCa. 2.
Evidence acquisition
This paper is based on a presentation given at a satellite symposium on PCa that was held during the 2009 EAU Congress on 18 March 2009 in Stockholm, Sweden. Data were retrieved from recent original articles, review articles, and abstracts on neoadjuvant or adjuvant HT to local treatment for PCa.
3.
Evidence synthesis
3.1.
What is the benefit of neoadjuvant hormone therapy to
radical prostatectomy?
According to a systematic review and meta-analysis of randomised trials of neoadjuvant HT in localised and locally advanced PCa, neoadjuvant HT to RP did not provide a statistically significant survival benefit over surgery alone (pooled relative risk: 1.00; 95% confidence interval [CI], 0.97–1.04; p = 0.95; Table 1) [2]. Moreover, Stephenson et al [3] developed a nomogram, with a concordance index of 0.8, to predict the long-term risk of PCa-specific mortality based on clinical data of 6398 patients who underwent RP from 1987 to 2005 in two US tertiary referral centres. External
validation was performed on 4103 patients from a separate institution. Fifteen-year PCa-specific mortality and allcause mortality were 12% and 38%, respectively. Surprisingly, besides biopsy Gleason grade, prostate-specific antigen (PSA), and year of surgery, neoadjuvant androgen-deprivation therapy (ADT) seems to be statistically significantly associated with PCa-specific mortality. 3.2.
What is the benefit of neoadjuvant and adjuvant hormone
therapy to radiation therapy?
HT is frequently combined with RT. Already >10 yr ago, Zietman et al [4], using an androgen-dependent breast cancer line (Shionogi tumour model), reported a significant reduction in the radiation dose required to control 50% of tumours when RT was combined with HT compared with RT alone. In addition, neoadjuvant HT resulted in a better efficacy than adjuvant HT to RT. With regard to clinical studies, the Radiation Therapy Oncology Group (RTOG) protocol 8610 was the first randomised phase 3 trial evaluating the effect of neoadjuvant HT to RT in 456 men with bulky (5 5 cm) T2-4 N0-X M0 tumours between 1987 and 1991 [5]. At a follow-up period of 10 yr, patients who received 2 mo of neoadjuvant ADT plus 2 mo of concurrent ADT combined with RT demonstrated statistically significantly fewer clinical failures ( p < 0.0001), distant metastases ( p = 0.006), and PCa-specific deaths ( p = 0.01) than patients who were treated with RT alone (Table 1) [5]. Although the 10-yr OS was 9% higher among men treated with neoadjuvant HT to RT versus RT alone, the improvement was not statistically significant. No differences in the risk of fatal cardiac events were observed between the treatment groups. Furthermore, several randomised phase 3 clinical trials investigated the value of adjuvant HT to RT in patients with high-risk localised or locally advanced PCa [6–9]. Bolla et al
Table 1 – Overview of randomised, controlled, phase 3 trials evaluating neoadjuvant or adjuvant hormone therapy to radical prostatectomy or radiation therapy for the treatment of prostate cancer Trial
Study population
Treatment
Result
Cochrane meta-analysis [2] RTOG 8610 [5]
Localised/locally advanced PCa T2–4 N0–X M0
Neoadjuvant HT to RP vs RP alone
No statistically significant improvement in OS
2 mo of neoadjuvant HT plus 2 mo of concurrent HT to RT vs RT alone
EORTC 22861 [10]
T1–T2 grade 3 or T3–T4 N0–1 M0 High-risk localised or locally advanced Localised T1c–2b N1–2 or pN1-2 or T2c–4 N0–2 M0 Locally advanced
Long-term (3 yr) adjuvant HT to RT vs RT alone HT + RT vs HT alone
Statistically significantly fewer 10-yr clinical failures, distant metastases, and PCa-specific deaths Better 10-yr OS but not statistically significant Significantly better 10-yr OS
SPCG-7/SFUO-3 [11] Canadian trial [14] EORTC 22961 [15]
RTOG 9202 [16]
Significantly lower 10-yr PCa-specific mortality
8-mo vs 3-mo neoadjuvant HT to RT 3-yr vs 6-mo adjuvant HT to RT
No increased 5-yr DFS, except in high-risk patients Better 5-yr OS
28-mo vs 4-mo HT to RT
Statistically significantly improved 10-yr DFS, DSS, local progression, distant metastasis, and biochemical failure No improved 10-yr OS, except in a subset of patients with Gleason score 8–10
PCa = prostate cancer; HT = hormone therapy; RP = radical prostatectomy; OS = overall survival; RTOG = Radiation Therapy Oncology Group; RT = radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; SPCG-7/SFUO-3 = Scandinavian Prostate Cancer Group Study 7 and Swedish Association for Urological Oncology 3; DFS = disease-free survival; DSS = disease-specific survival.
850
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
to apply only to men with no or minimal comorbidities. Among men with moderate or severe comorbidities, OS rates did not differ significantly ( p = 0.08). 3.3.
What is the optimal duration of neoadjuvant and adjuvant
hormone therapy to radiation therapy?
Fig. 1 – Ten-year results of the European Organisation for Research and Treatment of Cancer 22861 trial comparing long-term adjuvant hormone therapy plus radiation therapy (RT) with RT alone in patients with locally advanced prostate cancer [10]. OS = overall survival; RT = radiation therapy; HT = hormone therapy.
[7] demonstrated that HT starting on the first day of RT and continued for 3 yr was associated with a significantly better 5-yr OS than RT alone (78% vs 62%, p = 0.0002) in patients with T1-T2 grade 3 or T3-T4 N0-1 M0 PCa enrolled in the European Organisation for Research and Treatment of Cancer (EORTC) study 22861 between 1987 and 1995. Even at a longer follow-up period, the OS benefit was maintained in patients receiving long-term adjuvant HT (3 yr) to RT for locally advanced PCa without increasing cardiovascular toxicity (Fig. 1 and Table 1) [10]. It is still not proven whether the benefits are the result of hormoneinduced radiosensitisation or of an effect on micrometastases. Recently, Widmark et al [11] performed an open, randomised phase 3 study comparing HT with and without RT to assess the effect of RT. The Scandinavian Prostate Cancer Group Study 7 and the Swedish Association for Urological Oncology 3 (SPCG-7/SFUO-3) trial included 875 men from 47 centres in Norway, Sweden, and Denmark who were treated with life-long antiandrogen therapy alone or antiandrogens plus RT for high-risk localised or locally advanced PCa. Median follow-up was 7.6 yr. The cumulative incidence at 10 yr for PCa-specific mortality was significantly lower for patients who were treated with antiandrogens plus RT than for patients who received antiandrogen therapy alone (11.9% vs 23.9%, p < 0.001; Table 1). This significant difference also translated into improved OS. After 5 yr, urgency, urinary incontinence, and ED were slightly more frequent among patients who received antiandrogens plus RT. However, at a follow-up period of 4 yr, quality of life was comparable between the treatment groups. Although the addition of HT to RT may prolong diseasespecific survival (DSS) and even OS in patients with highrisk localised or locally advanced PCa, there is some evidence suggesting that HT is associated with an increased risk of cardiovascular events [12]. D’Amico et al [13] examined the impact of comorbidities on treatment outcome in 206 men who received RT alone or RT plus 6 mo of HT for localised but unfavourable-risk PCa. At a median follow-up of 7.6 yr, 36% of patients died. The OS was significantly increased in men randomised to RT and HT compared with RT alone ( p = 0.01), but this result appeared
Because the optimal duration of neoadjuvant or adjuvant HT has not yet been defined, several randomised trials have been performed to compare different durations of HT. In addition, shortening the period of HT may reduce the therapy’s costs and adverse events. This is the rationale for a Canadian multicentre, randomised, controlled phase 3 trial that evaluated the effect of 3 mo versus 8 mo of neoadjuvant ADT to RT in 378 men with clinically localised PCa between 1995 and 2001 [14]. A longer period of neoadjuvant HT to RT did not improve the 5-yr disease-free survival (DFS), except in a subgroup of high-risk patients (Fig. 2 and Table 1). In the EORTC randomised phase 3 trial 22961, Bolla et al [15] compared 6 mo with 3 yr of concomitant and adjuvant HT to RT in 970 patients with T1c-2b N1-2 or pN1-2 or with T2c-4 N0-2 M0 PCa. Noninferior OS was defined as a mortality hazard ratio (HR) 1.35 for short-term HT versus long-term HT. At a median follow-up of 6.4 yr, 24% of patients died. The 5-yr OS rate was 81.1% versus 85.1% (HR: 1.47; 95% CI, 1.12– 1.94) for patients who received 6 mo of HT compared with 3 yr of HT, respectively. Thus, noninferiority in terms of OS could not be proven in patients receiving 6 mo versus 3 yr of adjuvant HT to RT (Table 1). In addition, at 5 yr, clinical progression-free survival (PFS) and biochemical PFS were significantly worse for patients who were treated with 6mo adjuvant HT than patients randomised to 3-yr adjuvant HT to RT. In accordance with EORTC trial 22961, updated RTOG study 9202 reported that the addition of long-term HT (24 mo) improved outcomes in patients with locally advanced PCa who were treated with short-term HT (4 mo) before and during RT (n = 758) compared with no further HT (n = 763) in terms of 10-yr DFS (22.5% vs 13.2%; p < 0.0001), DSS (88.7% vs 83.9%; p = 0.0042), local progression (12.3% vs 22.2%; p < 0.0001), distant metastasis (14.8% vs 22.8%; p < 0.0001), and biochemical failure (51.9% vs 68.1%; p 0.0001; Table 1) [16]. A difference in OS at 10 yr was not
Fig. 2 – The effect of 3 mo versus 8 mo of neoadjuvant hormone therapy to radiation therapy in patients with clinically localised prostate cancer enrolled in a Canadian multicentre, randomised, controlled phase 3 trial [14]. HT = hormone therapy; RT = radiation therapy; DFS = disease-free survival.
EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 848–851
observed, except in a subset of patients with Gleason score 8–10 (45.1% vs 31.9%; p = 0.0061) in favour of longterm HT to RT.
851
[3] Stephenson A, Kattan MW, Eastham JA, et al. Prostate cancerspecific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era [abstract 1889]. J Urol 2008; 179:649. [4] Zietman AL, Prince EA, Nakfoor BM, Park JJ. Androgen deprivation
4.
Conclusions
and radiation therapy: sequencing studies using the Shionogi in vivo tumor system. Int J Radiat Oncol Biol Phys 1997;38:1067–70.
Neoadjuvant HT to RP does not seem to offer a survival benefit over RP alone in patients with localised or locally advanced PCa. Moreover, besides biopsy Gleason grade, PSA, and year of surgery, neoadjuvant HT before surgery may have a detrimental effect on PCa-specific survival. In contrast, neoadjuvant HT to RT appears to improve treatment outcomes, except OS, over RT alone in patients with locally advanced PCa. Adjuvant HT to RT can significantly improve OS compared with RT alone in high-risk localised and locally advanced PCa patients. Furthermore, compared with HT alone, the addition of RT to HT halved the 10-yr PCa-specific mortality in patients with high-risk localised or locally advanced PCa, with acceptable risk of adverse events. However, the OS benefit may pertain only to patients with no or minimal comorbidities. With regard to the optimal duration of neoadjuvant or adjuvant HT to RT, the EORTC 22961 trial failed to prove noninferiority in terms of OS of 6 mo of HT compared with 3 yr of HT to RT. In line with these data, it has been suggested that long-term HT should be the standard of care, especially in patients with high-risk PCa.
[5] Roach III M, Bae K, Speight J, 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 2008;26:585–91. [6] Pilepich MV, Winter K, Lawton C, et al. Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31 [abstract 1530]. Proc Am Soc Clin Oncol 2003;22:381. [7] Bolla M, Collette L, Blank L, 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 2002;360:103–8. [8] Hanks GE, Pajak TF, Porter A, 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 2003;21:3972–8. [9] Roach M, DeSilvio M, Lawton C, 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 2003;21:1904–11. [10] Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy:
Conflicts of interest
a phase III EORTC study [abstract 65]. Int J Radiat Oncol Biol Phys 2008;72:S30–1.
The author has no conflicts of interest.
[11] Widmark A, Klepp O, Solberg 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 2009;373:301–8.
Funding support
[12] Isbarn H, Boccon-Gibod L, Caroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits
The publication of this review was supported by Astellas Pharma Europe Ltd.
and risks. Eur Urol 2009;55:62–75. [13] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008;299:289–95.
Acknowledgements
[14] Crook J, Ludgate C, Malone S, et al. Final report of multicenter Canadian phase III randomized trial of 3 versus 8 months of
The author is grateful to Ismar Healthcare NV for assistance with writing the manuscript.
neoadjuvant androgen deprivation therapy before conventionaldose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;73:327–33. [15] Bolla M, De Reijke ThM, Van Tienhoven GJ, et al. Six-month con-
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