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European UrologyVolume 62, issue 2, pages e31-e48, August 2012
Addition of Radiotherapy to Long-Term Androgen Deprivation in Locally Advanced Prostate Cancer: An Open Randomised Phase 3 Trial
Accepted 23 March 2012, Published online 3 April 2012, pages 213 - 219
Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited.
To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients.
Design, setting, and participants
A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3–4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003.
ADT (11.25 mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external-beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo.
Outcome measurements and statistical analysis
The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates.
Results and limitations
ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p < 0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p < 0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p < 0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p < 0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period.
Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact.
The benefit of the addition of long-term adjuvant androgen-deprivation therapy (ADT) to local radiotherapy in patients with locally advanced prostate cancer was first demonstrated in 1997  and . Results from the European Organisation for Research and Treatment of Cancer (EORTC) 22863 and the Radiation Therapy Oncology Group (RTOG) 85-31 trials demonstrated significant improvements in disease control (biochemical, local, and distant) with combination therapy  and ; a benefit in 10-yr overall and disease-specific survival was later confirmed  and . The RTOG 92-02 study reported improved 10-yr prostate-specific and progression-free survival (PFS) comparing 28-mo androgen suppression with 4 mo ; in the EORTC 22961 study, 6-mo androgen suppression was inferior to 3-yr suppression for prostate-specific and overall survival at 5 yr . Two recent meta-analyses confirmed these results  and . The aim of the current study was to assess the possible benefits of the combined treatment on PFS.
2. Patients and methods
A prospective open-label randomised multicentre study was conducted in 40 centres in France (239 patients) and Tunisia (25 patients). Enrolment took place between March 2000 and December 2003. Men with histologically confirmed, locally advanced (T3–4N0) or pathologic pT3 prostate adenocarcinoma without documented nodes or metastases were eligible. Patients included had no prior treatment for prostate cancer, were < 80 yr of age, with a Karnofsky performance status of ≥70%, a life expectancy of ≥7 yr, and adequate haematological and hepatic function. Written informed consent prior to enrolment was received.
Patients were randomised to treatment with the luteinising hormone-releasing hormone (LHRH) agonist leuprorelin (11.25 mg subcutaneous depot injection every 3 mo) for 3 yr or to LHRH agonist plus external-beam radiation therapy. Oral flutamide (750 mg/d) was administered during month 1. ADT could be resumed during follow-up. Radiation therapy was initiated within 3 mo of randomisation and delivered with a four-field technique for the pelvic volume and a four- or six-field technique for the prostatic volume using high-energy photons (>10 Mv) and three-dimensional computed tomography (CT) planning. All patients received 46 ± 2 Gy given in 25 fractions over 5 wk to the whole pelvis and 22 ± 2 Gy given in 10–12 fractions over 2–2.5 wk in a volume encompassing the prostate gland and periprostatic tumour extension. In May 2011, the protocol was amended to increase the dose to the prostate from 68 ± 2 Gy to 70 ± 4 Gy. Delivery of radiation therapy was centrally reviewed (technique, target volumes, dose, and portals imaging) for all patients by four independent radiotherapists.
Pretreatment evaluations included medical history, physical examination, complete blood counts, biochemistry tests, prostate-specific antigen (PSA), performance status, and a complete radiologic assessment. A follow-up visit was performed 1 mo after the end of radiation (combined arm only) and every 6 mo for 5 yr. Thereafter, patients were followed annually for progression and survival. Follow-up assessments included a digital rectal examination and serum PSA. A transrectal ultrasound was recommended at 6 mo, 1, 3, and 5 yr. CT and bone scans were systematically performed in case of clinical or biologic progression. Adverse events were recorded throughout. Acute radiation toxicity was evaluated at the end of radiotherapy and after 6 mo according to the RTOG scale. Late radiation toxicity was evaluated throughout according to the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic scale.
2.3. Study end points
The primary end point was 5-yr PFS (biochemical or clinical) defined as the interval between randomisation and disease progression or death from any cause. Two definitions for the time of biochemical progression were evaluated. According to standard practices at the time of study initiation, the initial American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines, published in 1997 , were used, defined as an increase in PSA after nadir on two consecutive measurements, with a minimum interval of 3 mo between two determinations. Following revision of the ASTRO definition to an increase of ≥2 ng/ml above the PSA nadir at the ASTRO-RTOG consensus meeting in Phoenix, Arizona, in 2005 , an additional analysis of the primary end point was performed using the revised ASTRO-Phoenix definition. Locoregional clinical progression was defined as >50% increase in prostate volume compared with the lowest value by ultrasound, the appearance of a new palpable prostate lesion in the event of previous complete clinical normalisation, and identification of new regional lymph nodes by CT scan. Metastatic progression was defined by CT or bone scan. Secondary end points were disease-specific and overall survival, time to locoregional recurrence, time to distant metastases, and tolerance. Adverse events were classified according to MedDRA, v.11.1.
2.4. Statistical analysis
Statistical analyses were performed using SAS, v.8.2. Analyses were performed in the intent-to-treat population, defined as all randomised patients receiving at least one dose of study treatment (excluding flutamide) who completed at least one postbaseline visit. Multivariate analyses were performed using a Cox model with a 5% threshold from univariate analysis. Kaplan-Meier estimates were used to calculate time-related parameters. Cumulative incidence was also determined. Follow-up data were collected until July 22, 2009. The sample size (n = 256) was calculated to highlight a difference of at least 15% (hazard ratio [HR]: 0.456) in the percentage of PFS between the two strategies at M60 on an unilateral log-rank test with α risk of 5% and 80% power. The percentage of PFS in the combined treatment arm was estimated at 85% .
A total of 273 patients were included, 3 of whom withdrew consent before randomisation and 6 were ineligible, leaving 264 randomised patients; 131 patients received ADT alone and 133 combined ADT and radiotherapy. Pretreatment characteristics in the two groups were well balanced with regard to age, performance status, TNM staging, Gleason score, and baseline PSA (Table 1). Twenty-four patients (10 ADT and 14 combined) had undergone pelvic lymphadenectomy, with one in each arm identified as pN1. No statistical differences between arms in baseline characteristics were identified.
n = 131
|ADT plus radiotherapy
n = 133
|Age, yr, median (range)||71 (53–79)||72 (53–80)|
|Karnofsky performance status, %, median (range)||100 (70–100)||100 (80–100)|
|Clinical tumour stage, no. of patients (%)*|
|T3N0M0||122 (93)||123 (93)|
|T4N0M0||3 (2)||5 (4)|
|Biopsy pT3||5 (4)||5 (4)|
|Local Gleason score, no. of patients (%)|
|4–6||68 (52)||61 (46)|
|7||41 (31.3)||40 (30.1)|
|8–10||22 (16.8)||32 (24.1)|
|PSA, ng/ml, mean (SD)||51.8 (129.3)||41.5 (45.9)|
|PSA level, no. of patients (%)|
|<20 ng/ml||50 (38)||47 (35)|
|20–50 ng/ml||52 (40)||55 (41)|
|≥50 ng/ml||29 (22)||31 (23)|
|Pelvic lymph node dissection||10 (7.6)||14 (10.5)|
|Pathologically positive nodes||1 (0.8)||1 (0.8)|
|Metastatic disease||0 (0.0)||0 (0.0)|
* All patients were N0M0 (clinical and computed tomography criteria).
ADT = androgen-deprivation therapy; PSA = prostate-specific antigen; SD = standard deviation.
The intent-to-treat analysis was performed in the 130 ADT-alone patients (one patient withdrew consent prior to receiving any study drug) and 133 combined-therapy patients for the primary end point (Fig. 1). Six patients in the combined group received ADT but discontinued before receiving radiotherapy (two withdrew consent, two died, one progressed, and one for logistical reasons), leaving 127 patients who received combined therapy including radiotherapy. All but 4 of these 127 patients (96.9%) received a total radiation dose between 66 and 74 Gy. A total of 106 patients (83.5%) received a pelvic dose between 46 and 50 Gy. The median duration of radiotherapy was 55 d (range: 48–85 d). Hormone therapy was delivered as planned until progression for all patients. Median (range) in the ADT group was 2.5 (0.3–3.6) yr and 3.0 (0.3–3.5) yr in the combined group. Thirty-three patients treated in the ADT-alone arm received radiotherapy after progressing.
After a median follow-up of 67 mo (5.6 yr), PSA progression according to the initial ASTRO definition was observed in 102 patients (78.5%) treated with ADT and 23 patients (17.3%) with combined therapy. Similar results were reported with the ASTRO-Phoenix definition, with 89 ADT-alone patients (68.5%) progressing versus 19 combined-therapy patients (14.3%). Kaplan-Meier estimates demonstrated a significantly lower rate of patients censored for PFS at 5 yr with combined therapy than with ADT alone, for both the initial ASTRO and the ASTRO-Phoenix definitions. According to the initial definition, 60.9% of patients in the combined arm were censored for PFS at 5 yr compared with 8.5% with ADT alone (p < 0.0001; Fig. 2a), and 64.7% versus 15.4% for the Phoenix definition (p < 0.0011; Fig. 2b). The cumulative incidence according to the same definitions is shown in Figure 3.
Clinical progression was reported in 43 patients (33.1%) treated with ADT alone and in 13 patients (9.8%) treated with combined therapy. After a median follow-up of 67 mo, 55 patients had died, 24 patients (18.5%) treated with ADT alone and 31 (23.3%) with combined treatment, and 8 patients (4 in each arm) were lost to follow-up. No patients underwent radical prostatectomy. Nine patients in the hormone therapy group and five patients in the combined group had a palliative transurethral resection.
A statistically significant interaction between treatment and baseline PSA value was reported, with the risk of progression (ASTRO-Phoenix) 5.2 times higher (95% confidence interval [CI], 3.1–9.0; p = 0.04) when baseline PSA was between 20 and 50 ng/ml, and 10.1 times higher (95% CI, 5.0–20.5; p < 0.001) when PSA values were ≥50 ng/ml for the ADT-alone group (Fig. 2c).
At the time of analysis, a significantly lower incidence of locoregional progression was reported with combined therapy compared with hormone therapy alone (13 [9.8%] vs 38 [29.2%] patients). Cox analysis showed that combined therapy strongly favoured a reduced likelihood of locoregional progression with an HR of 3.6 (95% CI, 1.9–6.8; p < 0.0001). Median time to locoregional progression had not been reached (Fig. 4a).
A significant difference in metastasis-free survival was reported, with four patients developing distant metastases with combined therapy (3.0%) versus 14 patients (10.8%) with ADT alone (p = 0.018; Fig. 4b).
Median overall survival had not been reached in either treatment arm at the time of analysis (67-mo follow-up), and Kaplan-Meier estimates of mortality did not show a difference in overall survival rates between the two treatment arms: 71.4% and 71.5% for combined or ADT alone. Disease-specific mortality at 67 mo was also not significantly different between treatment groups. Nine patients receiving combination therapy and 18 receiving ADT alone died due to their prostate cancer, giving survival incidences of 93.2% versus 86.2% (p = 0.0586).
Genitourinary (GU) and gastrointestinal (GI) toxicities occurring during treatment, notably diarrhoea, pollakiuria, and dysuria, were more common with combined therapy than with ADT alone (250 vs 30 reports). Cardiovascular events occurred at a similar rate in the two arms (17 and 10 reports, respectively). Ten combined-therapy patients (8%) and three ADT-alone patients (2%) had reported serious adverse events related to the treatment. Four of these patients died, all in the combined therapy (no death was directly related to the treatment). Of the 127 patients who received radiotherapy, acute toxicity (RTOG) reported at the end of radiation therapy was mostly grade 2. Grade 2 or 3 GI toxicity was reported in 32 patients (25%), grade 2–4 GU toxicity in 17 patients (13%), and grade 2 or 3 dermatologic toxicity in eight patients (6%).
Acute toxicity persisted at a similar intensity 4 mo later in approximately half of the patients. Grade 2–4 toxicity reported at 6 mo included the bladder/urethra (29% in the combination arm vs 18% ADT alone), rectum (14% vs 2%), and small intestine/colon (13% vs 3%), and decreased gradually during follow-up, with bladder/urethra persisting longer than other toxicities.
The 5-yr PFS rates obtained in the current study with combined ADT and radiotherapy (60.9%, ASTRO; 64.7% ASTRO-Phoenix) can be compared with the 76% rate reported in the EORTC 22863 study  because the Gleason scores in the current study were higher and evaluation criteria differed. Addition of radiation to hormone therapy led to a significant improvement in 5-yr locoregional control and metastases-free progression, and the data suggest that PFS benefit is due to locoregional control. A recent review of published randomised studies using orchiectomy or LHRH advocates an interaction between local treatment and ADT . Convincing evidence of a survival benefit following local treatment in high-risk localised or locally advanced disease is reported, including patients with node-positive disease after radical prostatectomy. In a large retrospective analysis, increasing radiation doses resulted in better locoregional control and improved metastasis-free survival . Improved survival is likely due to a reduced incidence of late distant metastases developing as a result of locoregional progression.
The lack of routine lymphadenectomy in the current study would suggest that a reasonable proportion of patients were at risk of nodal invasion. Given the clear PFS benefit reported here, it is likely that these patients could benefit from combined therapy. A recent retrospective analysis demonstrating a significant survival advantage for both overall and relative survival in node-positive patients who had undergone radical prostatectomy is in line with this hypothesis , emphasising the importance of locoregional control.
The benefits in PFS with combined therapy in the current study did not translate into a survival advantage at 5 yr. Widmark et al. reported a significant improvement in overall survival with combined ADT and radiotherapy compared with ADT alone at 10 yr . Patients included in the study had less advanced disease and received hormonal treatment with flutamide as monotherapy, a therapeutic approach not widely used elsewhere. In that study, a notable increase in the difference between the treatment arms was seen between 7 and 10 yr, suggesting that longer follow-up in our study may be required. The National Cancer Institute of Canada-Clinical Trials Group/Southwest Oncology Group T94-0110 trial also showed a significant reduction in the mortality risk with the addition of radiotherapy to ADT after a median follow-up of 6 yr (p = 0.033), a trend that was more pronounced for specific survival (p = 0.001) . Despite the increase in urinary and digestive toxicities associated with combined therapy, the associated risk-to-benefit ratio remained favourable for combined therapy.
Limitations of the study are a relatively small population, and a longer follow-up is required. The use of radiotherapy to treat the 24 patients progressing after ADT alone may have had an impact on the survival outcome. Metastases and locoregional recurrence may have been underestimated due to the absence of systematic imaging evaluations at predefined time points. The radiotherapy regimen implemented matched the EORTC and RTOG studies but could be considered outdated in current treatment practices and might be improved on.
The addition of radiotherapy to 3-yr ADT significantly reduces the risk of progression and improves locoregional control in patients with locally advanced prostate cancer and can be considered a standard treatment option.
Author contributions: Nicolas Mottet had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mottet, Peneau, Mazeron, Molinie, Richaud.
Acquisition of data: Mottet, Peneau, Mazeron, Molinie, Richaud.
Analysis and interpretation of data: Mottet, Peneau, Mazeron, Molinie, Richaud.
Drafting of the manuscript: Mottet, Mazeron, Richaud.
Critical revision of the manuscript for important intellectual content: Mottet, Peneau, Mazeron, Molinie, Richaud.
Statistical analysis: None.
Obtaining funding: Mottet.
Administrative, technical, or material support: Mottet, Peneau, Molinie, Richaud.
Supervision: Mottet, Peneau, Mazeron, Richaud.
Other (specify): None.
Financial disclosures: Nicolas Mottet certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: All the authors received funding from Laboratories Takeda for an advisory/research role.
Funding/Support and role of the sponsor: Laboratories Takeda provided financial support for the running, monitoring, and statistical analysis of the study.
Acknowledgement statement: The authors acknowledge all the participating physicians, research support staff, and patients who participated in this study for their valuable contribution.
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a Department of Urology, University Hospital, St. Etienne, France
b Hôpital Clarac, Fort de France, Martinique
c Department of Radiotherapy, Hôpital Pitié-Salpêtrière, Paris, France
d Department of Anatomy and Pathology, Hôpital Saint Joseph, Paris, France
e Department of Radiation Oncology, Institut Bergonié, Bordeaux, France
© 2012 European Association of Urology, Published by Elsevier B.V.
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