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Combination of androgen deprivation therapy and radiotherapy for localized prostate cancer in the contemporary era Rolando M. D’Angelillo a,∗ , Pierfrancesco Franco b , Berardino De Bari c , Alba Fiorentino d , Stefano Arcangeli e , Filippo Alongi d a Radiation Oncology Campus Bio-Medico University, Rome Italy Department of Oncology, Radiation Oncology, University of Turin School of Medicine, Turin, Italy Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois – CHUV, Lausanne Switzerland d Radiation Oncology Department, Sacro Cuore-Don Calabria Hospital, Negrar-Verona, Italy e Radiation Oncology, Azienda Ospedaliera S. Camillo-Forlanini, Rome, Italy b

c

Received 14 February 2014; received in revised form 18 August 2014; accepted 1 October 2014

Contents 1. 2.

3.

4. 5.

Rationale and background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADT and EBRT in prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Short- course ADT and intermediate risk disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Long term ADT and high risk features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combining androgen deprivation therapy and brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. LDR series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Impact of ADT on clinical outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Impact of ADT on clinical outcomes according to dose delivered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. HDR series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . May ADT be administered to all patients? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Currently, androgen deprivation therapy (ADT) has a well-defined role when administered together with radiotherapy (RT): neo-adjuvant and concurrent combination for intermediate risk-disease and adjuvant therapy for high risk disease. Evidence of this association was generated by randomized trials designed and led approximately 30 years ago; thus the question which arises is how relevant and portable are these data in our current clinical practice? In the present review, we examine the pitfalls of these published randomized controlled trials, their relevance to present daily clinics, where high-dose external beam RT or brachytherapy is applied, as well as the adoption of ADT in patients with concomitant cardiovascular disorders. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Prostate cancer; Radiotherapy; Androgen deprivation therapy; Brachytherapy.



Corresponding author. Tel.: +39 3487287244; fax: +39 0622541433. E-mail address: [email protected] (R.M. D’Angelillo).

http://dx.doi.org/10.1016/j.critrevonc.2014.10.003 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

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1. Rationale and background Radiotherapy (RT) has been used for localized prostate cancer (PCa) for nearly a century [1]. In the dose escalation era, despite excellent outcomes after primary external beam radiotherapy (EBRT)+/− hormonal therapy for localized PCa, a proportion of patients with localized disease experienced a biochemical relapse [2–5]. This failure rate is related to well-known predictive factors [PSA, Gleason Score (GS), T-stage], as well as to intrinsic tumor radio-resistance and micro-metastatic disease at diagnosis [6–8]. Dose-escalated RT and agents enhancing radiation effect could significantly improve results. The use of hormonal therapy in PCa gained traction after the study by Huggins and Hodges [9] which demonstrated the androgen dependence of prostatic cells. Thereafter, pharmacologic castration was the preferred alternative to surgical castration, due to the advantages of avoiding potential orchiectomyrelated psychological effects, as well as the ability to restore the integrity of the hypothalamic–pituitary–testicular axis. Initially, androgen deprivation therapy (ADT) employed estrogens (diethylstilbestrol) [10]; however, the high rate of cardiovascular morbidity and mortality, due to firstpass hepatic metabolism and the formation of thrombogenic metabolites, led to a dramatic decrease in its use [11,12]. While ADT was considered the mainstay of treatment in metastatic disease [13,14], several randomized trials supported its use in combination with External-Beam Radiation Therapy (EBRT) for localized PCa and unfavorable risk features [15–18]. LH-RH agonists represent the benchmark in RT + ADT combination, although various classes of drugs, including LH-RH antagonists and anti-androgens, are currently available. The rationale of RT + ADT combination is based on the ability of androgen suppression to cause involutional changes in PCa cells and reduce tumor volume. Androgen ablation causes an 80% reduction in the number of epithelial cells in the normal prostate within 10 days, due to apoptotic cell death [19]. The pronounced dependence on androgen, however, is substantially mitigated in PCa, where the predominant effect of androgen ablation seems related to the inhibition of cell proliferation rather than apoptosis [20], resulting in a shift to quiescence [21], which in turn could theoretically diminish radiation sensitivity. The hypothesis that androgen ablation may act as a radiosensitizer despite the shift to quiescence has been confirmed in clinical trials showing that the combined use of radiation plus androgen ablation is superior than when used separately. [22–24]. This was initially proven in animal models demonstrating enhanced tumor control when ADT was incorporated to radiation within a neoadjuvant setting. Zietman et al. [25,26] showed that the radiation dose required to control tumors grown in nude mice decreased when the tumors were pretreated with androgen ablation: a reduction in the dose required to eliminate 50% of the tumor from 89 Gy with radiation alone to 60 Gy with orchiectomy followed by radiation one day later was observed. More

pronounced dose reductions (42 Gy) were seen when RT was delayed for 12 days after orchiectomy, but the same results were not observed when radiation preceded ADT. Joon et al. [27] showed a supra-additive interaction between androgen ablation and radiation through modulation of apoptosis. This effect was dependent on the timing of the two treatments, since the time course of apoptotic response to RT is conserved when androgen ablation precedes radiation. A crucial factor accounting for treatment failure and poor prognosis of PCa could be the anomalous and inefficient pattern of vascularization, leading to intermittent/chronic hypoxia [28,29]. Since inadequate tissue oxygenation is the prime trigger of angiogenesis, in which several angiogenic factors – including vascular endothelial growth factor and its receptors – are expressed [30], androgen deprivation can play a role in down regulating the expression of vascular endothelial growth factor, inducing apoptosis of endothelial cells and consequently decreasing vascularization [31–33]. ADT, therefore, may restore a transient “normalization” of tumour vascularization either by reducing leaky immature tumour vessels, causing perivascular cell deaths, decreasing interstitial pressure and increasing oxygenation, mostly during the neoadjuvant period [34]. A further field of interest is the monitoring of changes in tumor hypoxia during ADT: Hypoxia-inducible factor 1 (HIF1) is a transcription factor of high importance for PCa progression [35] and recent studies have shown that its suppression can play a significant role in ADT response without detectable changes in hypoxic fraction. Moreover, the expression of its alpha subunit (HIF1a) can act as a hypoxia biomarker in PCa [36], which could be helpful for planning RT initiation and potential use of hypoxia-targeted therapy. Currently, RT + ADT is a frequent combination therapy, but the adoption of dose escalated RT [2–5], along with longterm adverse effects of testosterone suppression [37–40], are considered crucial when identifying patients warranting the use of no, short-, or long-term ADT.

2. ADT and EBRT in prostate cancer Two major settings in combining ADT and EBRT can be defined: short-course ADT, given in neoadjuvant and concurrent intermediate-risk disease, and long-term ADT, given adjuvantly for 2–3 years in high and very high-risk patients [41]. 2.1. Short- course ADT and intermediate risk disease Five published trials investigating short-course ADT recorded a benefit for neoadjuvant and concurrent ADT over RT alone, increasing ADT prescription in the United States from 5% in 1989 to 85% in 2002 (Table 1) [42,43]. In RTOG 94-08 trial [44], 1979 patients with organconfined PCa and PSA ≤20 ng/ml were randomized to radiotherapy only (66.6 Gy/1.8 daily fractionation) or to

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Table 1 Randomised trials of radiotherapy and short-term versus no androgen deprivation therapy for prostate cancer. Author

No. pts

No. intermediate risk

Median fup (years)

ADT

RT dose

Endpoint

Results

Jones [44] Denham [45] D’Amico [46] Roach [47] Laverdière [48]

1979 818 206 456 161

1068 130 80 NR NR

9.1 10.6 7.6 11.9 5

0 vs 4 months 0 vs 3 vs 6 months 0 vs 6 months 0 vs 4 months 0 vs 3 vs 10 months

66.6 Gy 66 Gy 74 Gy 65–70 Gy 67

OS CSS, LC bPFS LC bPFS

Increased OS, bPFS, CSS Increased OS, CSS Increased OS, CSS Increased CSS, bPFS Increased bPFS

neoadjuvant and concurrent ADT (2 months + 2 months) plus the same RT schedule. RT + ADT recorded an improvement in 10-year Overall Survival (OS) and a decrease in the 10-year disease-specific mortality (DSM) over RT alone (62% vs 57%; p = 0.03 for 10yr-OS; 4% vs 8% for 10yr-DSM). Moreover, in a secondary not pre-planned analysis the benefit of RT + ADT was found relevant for intermediate-risk patients (1068 patients; 54% of the whole population) with an increase in the 10-year OS rate from 54% to 61% and a reduction in the 10-year DSM from 10% to 3%. The 10-years data from TROG 9601 [45] confirmed the role of short-course ADT, with better results in terms of PSA progression (60.4% vs 73.8%, with or without ADT) and local progression (15.7% vs 28.2%, with or without ADT), compared to RT alone (66 Gy/33 fractions). Unfortunately, only 16% (130/802) of patients in TROG 9601 had intermediate-risk disease. Studies by D’Amico, Roach and Laverdière [46–48] exploring the role of shortcourse ADT, included more advanced disease (70% in the D’Amico and Roach series and 36% in Laverdière’s), rendering any conclusion for short-course ADT in intermediate-risk patients difficult. Moreover, the improvement of local and PSA control by short-course ADT could be explained with the use of ineffective RT total dose. Presently, high-dose RT showed better results in phase III trials than lower doses [49–52]: the dose up to 78–80 Gy with standard fractionation is therefore generally considered the standard treatment [41]. This is a very important issue as it reduces the external validity of results, especially with regard to their relevance in current clinical practice. The evidence from these randomized controlled trials on RT plus short term ADT in intermediate risk patients, is not generally transferable in daily clinics due to the following factors: population is different (high risk patients have been enrolled as well), intervention and standard treatment have been improved by means of high dose RT, and the outcome (improvement in OS and DSS) could probably be over-estimated by the use of ineffective radiation dose in high risk population. In fact, data from MDACC phase III dose-escalation trial showed that PCa mortality in patients with intermediate risk disease and treated with high-dose RT without ADT is irrelevant [53].

However, no phase III randomized trials on high-dose RT + ADT were published, other than GETUG14. The preliminary results of this trial have been presented at ASCO 2011 [54], where 366 patients with intermediate-risk PCa had undergone high-dose EBRT (80 Gy) ± 4 months ADT. The trial was designed to test an improvement in biochemical and local tumour control by adding short-course ADT to high-dose RT. Even if ADT significantly increased the 3year biochemical progression-free survival rate (97% vs 91%; p = 0·04), the primary end-point was not reached (combined biochemical and local tumour control 92% vs 86%; p = 0·09). Furthermore, the trial was closed early due to poor accrual, highlighting that this issue is considered mildly relevant for current clinical practice. For this reason, some authors have published their large retrospective series on the use of ADT and high dose RT. In the large database analysis of MSKCC [55], an improvement in PSA relapse–free survival (PSA-RFS), in accordance with the use of short-course ADT, was recorded for 1074 intermediate-risk PCa even when high-dose RT (81 Gy) was administered. This data has been confirmed by Zumsteg [56], showing a benefit from 6-months ADT + high-dose RT over high-dose RT alone. In this series, 710 patients with intermediate risk PCa were treated with high dose RT (≥81 Gy) and neoadjuvant/concurrent ADT (357 patients): despite being more likely to have unfavorable disease (higher PSA levels, higher rate of Gleason score 4 + 3, presence of multiple National Comprehensive Cancer Network – NCCN – intermediaterisk factors), patients receiving ADT recorded improved PSA-RFS, DM and PCSM. Moreover, Gleason score 4 + 3 and ≥50% positive biopsy cores were other independent predictors of PCSM. The large heterogeneity of the intermediate-risk group (Gleason score 4 + 3 vs. 3 + 4, PSA level, one or multiple risk factors according to NCCN, percentage of positive biopsy cores), might explain these controversial results [57] when compared to PCa mortality in phase III dose escalation trials [53]. To overcome this issue, some groups tried to identify by means of nomograms [55] or clinical factors [56], different sub-risk categories in order to drive therapy according to different prognostic profiles. However, although it is logical to stratify patients according to certain clinical factors such as Gleason score (3 + 4

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Fig. 1. Biochemical failure in RTOG 92-02 trial (modified from [14]).

vs. 4 + 3), percentage of positive cores ( 30 ng/ml at diagnosis.

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Fig. 3. Clinical PFS in EORTC 22863 trial (modified from [15]).

EORTC 22961 enrolled 970 patients in less than 5 years, with a great proportion of T3–4 disease (77%) and less than 20% of GS 8–10. Finally, EORTC 22863, the most solid trial favoring longterm ADT, enrolled 415 patients in a 8.5 year time with 90% having very advanced disease (T3–4 and a high GS in >50% of patients). This trial has similar characteristics to RTOG 85-31 [61] where 977 patients were enrolled, ninety percent of which had T3–4 stage and 33% a GS of 8–10. In this trial, patients after RT (total dose 65–70 Gy) where randomized to immediate ADT or ADT at relapse. The trial had positive findings for immediate ADT for all 10-year end-points (local failure, DM, DSS, OS), in particular with an improvement in survival in patients with a GS of 7–10. The updated 2009 secondary analysis [59] revealed that patients administered ≥5 years with ADT recorded the highest results in terms of OS, DFS and DM rate. Moreover, long-lasting ADT, as the only treatment of advanced disease without RT, was explored in the Canada–UK Trial PR.3/PR7 [62], where 1205 patients were randomized to long-lasting ADT only or ADT + RT up to a total dose of 65–69 Gy. Both survival end-points (OS and DSS) recorded a benefit at 7-years with 66% and 79% in ADT

group (OS and DSS) vs. 74% and 90% for ADT + RT group (p = 0.03 for OS; p = 0.0001 for DSS). In clinical practice, results of randomized trials were generally transferred in the adoption of 2–3 years of ADT plus RT, which is always required in advanced non-metastatic disease. As radiation dose is currently over 70 Gy and as patients are better staged (MRI for local staging and PET/CT for nodal metastases), do we still need ADT? Looking at the long-term results of a dose-escalation trial [63], even in an high-dose arm (78 Gy) a PSA recurrence occurs in 21% of patients in the high-risk group with 8% of local recurrence and 4% of nodal and distant progression. Thus, even with high-dose RT, high-risk disease demands ADT. The correct duration of ADT is still far from being defined, and according to the four most important randomized trials, three different categories can be defined and ADT administered accordingly (Table 3). The first group included patients with one high-risk feature (cT3a; GS = 8–10; PSA > 20 ng/ml) where patients could be treated according to RTOG 92-02 [58] with 4month neoadjuvant and concurrent ADT followed by 2-year ADT.

Table 2 Characteristics of the Patients for 3 randomized trials exploring long-term ADT + RT (see text for details). Patients’ characteristic

RTOG 92-02

EORTC 22863

EORTC 22961

Eligible patients (#) Enrollement time (yrs) Clinical stage T3-4 N-Stage positive Gleason Score 8-10 PSA @ diagnosis

1521 2.9 54.5% 4.2% 23.7% >30 ng/ml: 32.9%

415 8.5 89.6% 3.8% 31.5% >20 ng/ml: 56.6%

970 4.6 77.7% 8.4% 19.1% Median value: 18.8

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Table 3 proposal for ADT duration (see text for details). Definition

ADT

Refferring trial

Single High risk Multiple High risk or T3b T4 N0 M0 Any T N + M0 (PSA > 150 ng/ml)

28 months 36 months

RTOG 92-02 EORTC 22863

At least 3 years, or long lasting

RTOG 85-31 PR.3/PR7

(mainly for seed implants) regarding the need for cytoreduction if initial prostate gland volume overpasses 60 cm3 to avoid pelvic arch interference and to enhance isotope distribution, improving dosimetry [66]. Conversely, as high-risk PCa patients have an increased risk of microscopic pelvic lymph-nodes spread, several groups investigated the role of adjuvant ADT to supposedly provide biochemical control and survival benefit. 3.1. LDR series

The second group, with multiple high-risk features or with cT3b disease only, could be classified as patients similar to EORTC 22863 [59] and long-term ADT (3 years, considering neoadjuvant and concurrent phase if applied) could be adopted. Finally, very high-risk features (T4 disease/N + disease/ very high PSA), could be allocated, according to RTOG 8531 [61] and PR.3/PR7 [62], very long ADT administration (over 3 years) or the long-lasting approach. These proposals, which seem to reflect the authors’ beliefs more than strong evidence from literature, represent an attempt to fit the real patient into those categories evaluated by different randomized trials.

3. Combining androgen deprivation therapy and brachytherapy Brachytherapy (BRT) is a safe and effective monotherapy treatment modality for low-risk PCa, providing more comparable outcomes than EBRT and radical prostatectomy (RP). Conversely, its role in intermediate- to high-risk patients has to be further defined with regard to integration with other treatment modalities (supplemental EBRT and/or androgen deprivation therapy (ADT). BRT implies two separate approaches: low-dose-rate (LDR) permanent seed implants (125 I; 106 Pd) and temporary interstitial conformal high-dose-rate (HDR) with a stepping source (192 Ir). LDR-BRT represents an efficient outpatient-based monotherapy for low-risk and selected intermediate-risk PCa patients or a combination strategy (with EBR + ADT) in case of high-risk features [65]. HDR–BRT is a means to perform absolute (increasing total nominal dose) and radiobiologic (increasing dose per fraction) dose escalation for high-risk localized PCa, together with EBRT + ADT [64]. The association of ADT and BRT is controversial as it has been used mainly empirically, with consistent variations among treating centers with outcomes analyzed on retrospective mono/oligoinstitutional series. Evidence-based decisional algorithms for a proper combination of ADT and BRT are still lacking, in the absence of specific prospective randomized trials. Furthermore, the timing of association (timeline and duration) has yet to be established. The neoadjuvant setting for ADT (also for low-risk patients), reported in several series, comes from previous American Brachytherapy Society suggestions

3.1.1. Impact of ADT on clinical outcomes D’Amico et al evaluated outcomes of 1342 high-risk PCa patients (PSA > 20 ng/ml, GS > 8, stage > cT3-T4) with a life expectancy ≥10 years, submitted to seed implants + EBRT (867 pts; 65%) + ADT (904 pts; 67%) with LH-RH analogue + AA (median duration: 4 months) [67]. Specifically, 19% were treated with combined BRT-ADT, while 48% with a tri-modality approach (BRT–EBRT–ADT). Patients undergoing supplemental ADT and EBRT were more likely to have palpable localized or locally advanced disease, GS > 7, and all three risk factors, as well as a higher baseline probability of prostate cancer specific-mortality (PCSM). In spite of this unfavorable selection bias, authors found a significant reduction in the risk of prostate cancer death with an adjusted hazard ratio (AHR) of 0.32 and a non-significant reduction in all-cause-mortality (ACM) for patients receiving supplemental ADT and EBRT vs BRT alone. This was not true for patients receiving supplemental ADT-only or supplemental EBRT-only. ADT duration did not predict PCSM in both unadjusted and adjusted analysis. PCSM comprised 16% of all mortality. Patients undergoing tri-modality treatment had a longer time to PCSM, compared to BRT alone; this was not confirmed for patients treated with ADT or EBRT. After adjusting for GS, initial PSA, age, year of BRT, patients undergoing tri-modality therapy had a near-significant reduction in PCSM risk. Shilkrut et al, retrospectively analyzed 958 high-risk PCa patients (PSA > 20 ng/ml; GS > 8; cT3-T4) treated with doseescalated EBRT (75–81 Gy) or combined EBRT/LDR-BRT, delivered with 103 Pd or 125 I [68]. ADT consisted of LH-RH analogue ± AA. Patients in the EBRT group were older, with higher PSA level and T-stage at diagnosis, lower GS and more likely to have 2–3 high risk features. ADT was more frequently used in the EBRT group (85%; median duration: 22 months) than in the BRT group (76%; median duration: 12 months). Patients receiving longer ADT had higher risk disease than those having shorter ADT and higher CAPRA score (University of California San Francisco Cancer of the Prostate Risk Assessment tool) a tool combining PSA, T-stage, GS and age. In multivariate analysis (controlling for age/PSA/Tstage/GS/RT regimen/receipt and duration of ADT), the addition of ADT provided a lower BF with a more favorable HR at each incremental increase of ADT duration (24 months), which was

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statistically significant for each group, but higher for patients receiving ADT > 24 months (p = 0.0001; HR: 0.33; 95%). The same benefit was noted with respect to CSS, for ADT > 24 months. With ADT as a continuous variable, at each 1-monthduration increase, an association was found with a lower BF (HR: 0.98; p = 0.04; 95%) and cancer specific mortality (HR = 0.97; p = 0.01; 95%). In the group submitted to BRT + EBRT, long term ADT (>24 months) was associated with reduced BF (HR = 0.21; p = 0.03; 95%). Conversely, a reduction in cancer specific mortality adding ADT, either as a categorical (HR = 0.54; p = 0.42; 95%) or a continuous variable (HR = 0.97; p = 0.20; 95%) was not observed. The addition of ADT was associated with lower BF (higher with longer ADT-duration) and consistent with both modalities. Longterm ADT also decreased PCSM in all patients and well as in those receiving EBRT-only. This was not true for BRT + ADT patients with low absolute risk of PCSM (19 deaths; 4%): it was difficult for authors to demonstrate an improvement, because 76% of patients already received ADT (median: 12 months). The reduction in PCSM with ADT translates into a 40% relative improvement of CSS for short-term ADT (24 months). Potters et al reported data on 612 clinically confined PCa patients submitted to seed implants (125 I or 103 Pd + supplemental EBRT) [70]. 177 (29%), with a prostate volume > 60 ml underwent pre-implants ADT for downsizing (3–4 months: 70%; 4–8 months: 20%). Univariate analysis failed to demonstrate any BFFS improvement with ADT. A retrospective computer-generated matched-pair analysis, matching 263 patients with homogeneous characteristics (GS, initial PSA, clinical stage, supplemental EBRT and isotope) according to positive univariate prognostic factors found no difference in terms of BFFS according to ADT administration (p = 0.935), regardless of duration, even if ADT patients had a larger prostate volume (48.6 cm3 vs 37.8 cm3 ; p = 0.4). A subgroup analysis (GS, initial PSA, clinical stage, EBRT use) failed to demonstrate any outcome impact for ADT. Merrick et al treated 938 PCa patients (cT1b-cT3a; mostly intermediate-risk) with seed implants [71]. ADT was administered for suboptimal geometry, urinary obstructive symptoms or poor prognosis to 382 patients (41%) on a short(6 months; 11.2%). Low risk patients had ADT for 200 Gy patients were considered, those differences disappeared (8% vs 4%; p = 0.292). In logistic regression analysis, ADT had a significant effect in achieving a negative biopsy (HR = 0.205; p > 0.001), but not in BED2Gy > 200 Gy patients.

3.2. HDR series Galale et al reported results of a pooled analysis of three prospective single-institution trials involving 611 clinically staged and localized PCa [72]. Patients were treated with supplemental EBRT (45–50 Gy to pelvis). During EBRT, a HDR boost (2–4 fractions) was performed for an overall treatment time of 5–6 weeks. Several protocols were followed: 2 fractions delivered with different doses to different volumes (15 Gy each to the peripheral McNeal zone or 8–9 Gy to the entire PG); fractions with a progressive dose per fraction increase (3–4 Gy) or 2 fractions with progressive increase (5.5 Gy–11.5 Gy). Up to 29% of patients (177) received ADT for prostate downsizing (median duration: 4 months). No difference was found in terms of OS, CSS, DFS and biochemical control according to ADT on the whole cohort, on a subset analysis after stratification for risk groups (intermediate- to high-risk patients only) and even stratifying for 1 or a combination of 2–3 of the factors predicting poor prognosis (stage > T2b, PSA > 20 ng/ml, GS > 8). At

Please cite this article in press as: D’Angelillo RM, et al. Combination of androgen deprivation therapy and radiotherapy for localized prostate cancer in the contemporary era. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.003

Treatment yrs

Mean FU

Risk category (NCCN)

EBRT volumes

EBRT dose (cv)

Isotope

611

1986–2000

60 months

I-H: 547 pts

PG-SV-Pelvic LN

45.6–50 Gy

Astrom et al. [73]

214

1988–2000

12 months

I-H: 134 (63%)

PG-SV-Pelvic LN PG-SV

Martinez et al. [74]

507

1986–2000

58 months

I-H: 507 (100%)

LDR series D’Amico et al. [75]

218

1989–1997

41 months

Potters et al. [70]

612 Match-paired: 216

1992–1997

Potters et al. [76]

1449

1992–2000

Dose/Fractions

ADT timing

ADT duration

ADT type

ADT pts

Outcomes

192 Ir

16.5–30 Gy/2–4 fr (ICRU58)

Neoadjuv/Concom

Mean: 4 months

50 Gy

192 Ir

20 Gy/2 fr

Neoadjuv/Concom

Mean: 5 months

NR

177

CAB; AA; GnRH an

150 (70%)

5 yr CSS: 95–99%; BFFS: 69–88% 5 yr CSS: 86–100%; BFFS: 56–87%

PG-SV-Pelvic LN

45.6–50 Gy

192 Ir

16.5-30 Gy/2-3 fr (ICRU58)

Neoadjuv/Concom

Mean: 6 months

NR

177 (35%)

5 yr BFFS: 74-76%; CSS: 90-98%

I-H: 95 (44%)





103 Pd

115 Gy (mPD)

Neoadjuvant

Mean: 3 months

Induction AA + LH-RH an

152 (70%)

5 yr BFFS: 45–60%

42 months

NA

– PG-SV-Pelvic LN

– 41.4–45 Gy

125 I or 103 Pd

144–120 Gy (TG43; NIST1999) 108–90 Gy (TG43; NIST1999)

Neoadjuv/Concom

Range: 3–8 months

NR

177 (29%) Match-paired: 132

5 yr CSS: 98%; BFFS: 86.5%

82 months

I-H: 972 (67%)

– PG-SV-Pelvic LN

– 41.4–45 Gy

125 I [1,0]or 103 Pd

144–136 Gy (TG43; NIST1999) 108–102 Gy (TG43; NIST1999)

Neoadjuv/Concom

Mean: 5.2 months

NR

400 (28%)

12 yr CSS: 93%; BFFS: 63–78%

Prada et al. [77]

734

1999–2006

55 months





145 Gy (TG-43)

Neoadiuv/Concom

Range: 3–4 months

NR

313 (43%)

10 yr BFFS: 65–84%

Lee et al. [78] Beyer et al. [79]

201 2378

1990–1998 1988–2001

42 months 49 months

I-H: 247 pts (34%) I-H: 201 (100%) I-H: 1243 (52%)

125 I

– – PG-SV-Pelvic LN

– – 45 Gy

125 I or 103 Pd 125 I or 103 Pd 125 I or 103 Pd

160–124 Gy (TG-43,NIST1999) 145-120 (TG-43; NIST-1999) 120-90 (TG-43; NIST-1999)

Neoadjuvant/Concom/Adjuv Neoadjuvant/Concom/Adjuv

Range: 5–6 months Range: 3–12 months

CAB LH-RH an ± AA

201 (100%) 464 (20%)

5 yr BFFS: 62–85% 10 yr CSS: 77–85%

Merrick et al. [80]

668

1995–2001

62 months

I-H: 441 (66%)

– PG-SV-Pelvic LN

– 45 Gy

125 I or 103 Pd

145-125 (mPD; TG-43-NIST1999) 110-90 Gy (mPD; TG-43-NIST1999)

Neoadjuvant/Concom/Adjuv

Mean: 7 months

CAB

227 (34%)

8 yr BFFS: 88–98%

Merrick et al. [71]

938

1995–2002

65 months

I-H: 609 (65%)





125 I or 103 Pd

145-115 (mPD)

Neoadjuvant/Concom/Adjuv

Mean: 7.5 months

CAB

382 (41%)

Merrick et al. [81]

350

1995-2000

50 months

I-H: 350 (100%)

– PG-SV-Pelvic LN

– 20-45 Gy

125 I or 103 Pd

145-115 (mPD)

NeoA/Conc ± Adjuv

Mean: 4 or 8-12 months

NR

141 (40%)

10 yr BFFS: 93–97%; CSS: 93–99% 6 yr BFFS: 79-100% 110-90 Gy (mPD)

Fang et al. [82]

174

1995–2005

78 monhts

H: 174 (100%)

– PG-SV-Pelvic LN

– 45 Gy

125 I or 103 Pd

145-125 (mPD) 100-90 Gy (mPD)

Neoadjuvant/Concom/Adjuv

Mean: 12 months

CAB

113 (65%)

10 ys BFS: 93%; CSS: 95%

Shilkrut et al. [68] Stock et al. [83] Stock et al. [69]

448 181 2427

1995–2010 1994–2006 1990–2010

63 months 65 months 78 months

H: 448 (100%) H: 181 (100%) I-H: 1341 pts (55%)

PG-SV-Pelvic Ln PG-SV-Pelvic Ln – PG-SV-Pelvic LN

45–50.4 Gy 39.6–59.4 Gy

125 I or 103 Pd 103 Pd 125 I or 103 Pd

Neoadjuvant/Concom/Adjuv Neoadjuvant/Concom/Adjuv Neoadjuvant/Concom/Adjuv

Median: 12 months Median: 9 months Range: 3–30 months

NR LH-RH an ± AA LH-RH an ± AA

342 (76%) 181 (100%) 1328 (55%)

8 yr BFFS: 82%; CSS: 95% 8 yr BFFs: 73%; CSS: 87% 10 yr BFFS: 86%;

45 Gy

108-100 (median) 63–100 Gy (NIST1999) 160–124 Gy (TG-43; NIST1999) 120–100 Gy (TG-43; NIST1999)

D’Amico et al. [67]

1342

1991–2005

61 months

H: 1342

– PG-SV

– 45 Gy

125 I,103 Pd or131 Cs

144–108–115 Gy 108–90–100 Gy

Neoadjuvant

Median: 4 months

LH-RH an ± AA

904 (67%)

5 yr PCSM: 4–16%

ARTICLE IN PRESS

Pts

HDR series Galalae et al. [72]

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Table 4 Clinical series investigating BRT and ADT association.

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univariate and multivariate analysis, ADT did not predict BF. 3.3. Remarks Almost all studies providing data on the role of combination ADT + BRT come from retrospective evaluations or retrospective secondary analysis of prospective trials with different primary endpoints (Table 4) [67–82]. Even if most of these analyses were adjusted for established PCa prognostic factors, evidence of the association between ADT and survival outcomes requires a prospective randomized trial in order to balance known and unknown prognostic between treatment arms, avoiding selection bias. The University of British Columbia Androgen Suppression Combined with Elective Nodal and Dose-Escalated RT trial, is presently ongoing, comparing dose-escalated EBRT (78 Gy) vs EBRT + BRT boost (125 I) both with 12-months ADT [84]. This study will provide methodological consistency to this clinical debate.

4. May ADT be administered to all patients? The most prominent concern regarding ADT administration should focus on cardiovascular morbidities, since evidence derived from pooled analyses of randomized trials and large patient cohort studies have observed an increased risk of fatal and nonfatal cardiovascular events in advanced age PCa patients [40,85,86]. Thus, since age usually comes with co-morbid illnesses, the general survival benefit observed combining RT and ADT might have different consistencies according to the subset of patients, evaluated on associated co-morbidities. D’Amico et al performed a post-randomization hypothesis-generating analysis within a phase III randomized trial comparing RT alone vs RT + ADT in men with localized unfavorable-risk prostate cancer [85]. OS was analyzed according to subgroups defined by the level of co-morbidities by the time of randomization, evaluating the eventual interaction between co-morbidity level and treatment group in terms of ACM. Results suggested that the survival benefit given by the combination of RT + ADT was confined to patients with no or minimal co-morbidity, while patients with moderate to severe co-morbidity had a nullified OS benefit. To better clarify which co-morbid condition would be responsible for this eventual loss in survival, the same group performed a single-institution retrospective analysis assessing whether 4-months-neoadjuvant ADT (before BRT) would affect ACM in patients with cardiovascular co-morbidities such as coronary artery disease-induced (CAD) conditions: congestive heart failure (CHF) or myocardial infarction (MI) or CAD risk factors (diabetes mellitus, hypercholesterolemia and arterial hypertension) [86]. An increased risk in ACM was observed with neoadjuvant ADT in patients with CAD-induced CHF or MI (26.3% vs 11.2%; adjusted HR: 1.96). This finding was not confirmed for

9

patients with no co-morbidities or a single CAD risk factor (10.7% vs 7%; adjusted HR: 1.04). The negative impact of 4 months-neoadjuvant ADT on all-cause mortality was further confirmed in low-risk PCa patients with at least one CAD risk factor treated with BRT + EBRT + ADT. This was not true in patients with low risk PCa patients with no risk factor or in intermediate- to high-risk PCa patients [87]. Using a Markov decision analysis model, Lester-Coll et al compared quality-adjusted life expectancy (QALE) in high-risk PCa patients receiving exclusive EBRT vs EBRT + short-term (6 months) or long-term (36 months) ADT, after stratification for cardiovascular comorbidities and age [88]. Patients with a history of MI had a 0.1–0.2 decrease or a 0.5–0.6 decrease in quality-adjusted years (all ages) with short-term or long-term ADT, respectively, compared to exclusive EBRT. Patients without MI had a QALE benefit with ADT (short- and longterm) vs exclusive EBRT. Long-term ADT was found to provide a QALE improvement for PCa patients aged 50–60, except those with MI; for PCa patients aged 70, with 4 CAD risk factors, ADT did not provide any QALE benefit. PCa patients are generally old and might have co-morbid illnesses. Cardiovascular co-morbidities (CHF and MI) and CAD risk factors (diabetes mellitus and arterial hypertension) might increase the risk of ACM in PCa patients, in addition to age itself and unfavorable PCa prognostic factors [89]. These co-morbid prognostic factors might be reliable predictors of mortality from competing causes and might be included in the clinical decision-making process to select the optimal management option for every single PCa patient. Future trial design for PCa patients having ADT as part of the treatment should include pre-randomization stratification according to CAD risk factors, CHF and MI in order to clarify the effects of therapy in different co-morbid patient’s subgroups. Finally, the ability to treat patients with salvage radiotherapy for intra-prostatic [92] or nodal recurrence [93] could reduce the adoption of ADT in patients with high-risk cardiovascular features [90,91]. 5. Conclusion The addition of ADT to radical radiotherapy in PCa, even though considered a well-defined and standard treatment, should be taken into consideration in order to place the right patients into the right categories. Personalized treatment, according to new frontiers of staging, treatment and co-morbidities, warrants further investigation to strengthen this cornerstone of combined therapy in PCa [94]. Conflict of interest All authors declare no financial and personal relationships with other people or organisations that could inappropriately influence their work.

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Please cite this article in press as: D’Angelillo RM, et al. Combination of androgen deprivation therapy and radiotherapy for localized prostate cancer in the contemporary era. Crit Rev Oncol/Hematol (2014), http://dx.doi.org/10.1016/j.critrevonc.2014.10.003

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Combination of androgen deprivation therapy and radiotherapy for localized prostate cancer in the contemporary era.

Currently, androgen deprivation therapy (ADT) has a well-defined role when administered together with radiotherapy (RT): neo-adjuvant and concurrent c...
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