Does Local Treatment of the Prostate in Advanced and/or Lymph Node Metastatic Disease Improve Efficacy of Androgen-Deprivation Therapy? A Systematic Review

doi:10.1016/j.eururo.2010.05.027

European Urology

Volume 58, Issue 2, August 2010, Pages 261-269

https://doi.org/10.1016/j.eururo.2010.05.027 Get rights and content

Abstract

Context

Androgen-deprivation therapy (ADT) plays a pivotal role in the management of locally advanced and metastatic prostate cancer (PCa). When and for how long to apply ADT have remained controversial issues.

Objective

To review randomised studies of ADT (orchiectomy or luteinising hormone-releasing hormone analogues) in PCa—both immediate and deferred/adjuvant studies—to elucidate a possible interaction between local treatment and ADT.

Evidence acquisition

Published randomised studies on ADT in various stages of PCa were included in this review.

Evidence synthesis

Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival (OS; hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.83–0.97) and cancer-specific survival (CSS; HR: 0.79; 95% CI, 0.71–0.89). In contrast, ADT as an adjuvant to radiation therapy in patients with high-risk localised disease or locally advanced disease was associated with substantial OS and CSS benefits. A similar benefit was seen in patients with proven systemic disease (node-positive patients after radical prostatectomy). Overall, the data suggest a clinically important survival benefit (HR for OS: 0.69; 95% CI, 0.61–0.79) when a local treatment has been applied to the primary tumour. Possible mechanisms of this therapeutic effect are discussed.

Conclusions

We conclude that an interaction between local treatment and ADT is suggested by this systematic review. In patients with advanced and aggressive disease who are at a high risk to die from PCa and who are treated for their primary tumour with curative intent, immediate and sustained ADT improves OS and CSS significantly. The local therapy in T3 and/or lymph node–positive disease is an essential part of the optimal treatment. However, this intensive treatment is unnecessary in a substantial number of patients with T3 and/or N1 disease with a slow natural history or high competing death risk.

Introduction

The optimal timing and duration of hormone treatment in prostate cancer (PCa) has been subject to debate since its description. Hodges and Huggins are often referred to as the first to describe this treatment in 1941 [1]. In a prior publication in 1940, Dr. Paul Niehans from Switzerland described PCa and prostatic hyperplasia as a result of hormonal disease, which he treated by scrotal surgery [2]. Two Cochrane reviews have addressed the issue of immediate versus deferred androgen-deprivation therapy (ADT) [3] and of adjuvant ADT [4] in various stages of PCa. Both Cochrane reviews address the efficacy of a longer or shorter episode of ADT during the course of PCa, mostly using luteinising hormone-releasing hormone (LHRH) agonists or castration as an intervention. These reviews have, however, reached contrasting conclusions, implying that immediate ADT offers little benefit, while adjuvant ADT appears to prolong survival significantly. The contrasting results in the various studies are a frequent cause of debate. Despite the differences between immediate and deferred ADT studies on the one hand and adjuvant trials on the other hand, we think it is important to discuss these studies collectively, because exposure to ADT is the only variable that has been modified in these randomised studies.

The radiosensitising effect of ADT is generally accepted as an important explanation for improved outcome in radiation therapy (RT) trials that used concomitant ADT. In RT studies, the radiation dose to the prostate ranged between 65 and 70 Gy, and the radiation field to the regional nodes has varied. Importantly, that range of radiation dose is considered suboptimal according to today’s standards. Indeed, dose escalation studies have shown superior results in localised disease for doses up to 79 Gy conformal RT over the standard dose (70.2 Gy) [5]. Androgen withdrawal is reported to reduce tumour hypoxia, which might play a role in the increased efficacy of RT, although the exact mechanisms are currently unclear [6].

Apart form a possible radiosensitising effect, a systemic effect of adjuvant ADT must be responsible for some of the observed results. In a study reported by Messing et al (node-positive patients after radical prostatectomy [RP]), improved survival was reported following immediate ADT [7]. Furthermore, a recent study was published on the optimal duration of adjuvant therapy [8]. In this study, patients with locally advanced disease were randomised between ADT concomitant and adjuvant to three-dimensional conformal RT (70 Gy) during 6 mo in one arm and the same combination with the addition of 2.5 yr of ADT in the other arm. A better overall survival (OS) following 3 yr of ADT was reported (death rate was 15.2% vs 19%, respectively). The observed hazard ratio (HR) for OS was 1.42, favouring the longer ADT group [8]. Although local treatment was identical in this study, 2.5 yr of additional ADT improved OS and cancer-specific survival (CSS) more than what we knew from trials addressing the immediate versus deferred ADT issue. These results initiated the current systematic review, the objective of which was to review randomised studies of ADT (orchiectomy or LHRH analogues) in PCa to elucidate a possible interaction between local treatment and ADT.

Section snippets

Evidence acquisition

All published results from 1970 to the present for randomised studies on immediate versus deferred and adjuvant ADT in PCa (Medline, Embase) reporting CSS and OS were selected for this systematic review. The trials addressing the immediate versus deferred and adjuvant designs, respectively, seem sufficiently similar to allow a literature-based analysis. This review obviously cannot avoid the publication bias and problems resulting from differences in patient characteristics, treatment schemes,

Evidence synthesis

Five studies of immediate versus deferred ADT were included (section A in Table 1) [17], [18], [19], [20], [21], [22], [23]. For the VACURG 1 study, only the treatment groups with orchiectomy and/or placebo were included; the groups receiving diethylstilbestrol were not. The average delay in treatment in the control arm was reported in four trials and ranged from 1.8 to 7 yr. Five adjuvant studies are listed under B in Table 1[7], [24], [25], [26], [27], all making use of castration or LHRH

Conclusions

Several studies have shown that adjuvant ADT (ranging from 6 mo to life-long) can importantly alter OS and CSS in high-risk PCa patients of various stages, especially locally advanced disease and lymph node–positive disease. Irradiation or surgical removal of the primary tumour appears to be a necessary condition to fully benefit from prolonged (ie, >6 mo) ADT. Although many clinicians hesitate to offer a local treatment to a patient who cannot be cured, the current analysis suggests that this

References (36)

C. Huggins et al.
Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941
J Urol
(2002)
E.M. Messing et al.
Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy
Lancet Oncol
(2006)
M.P. Wirth et al.
Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph node-negative prostate cancer
Eur Urol
(2004)
G.K. Zagars et al.
Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study
Int J Radiat Oncol Biol Phys
(1988)
P. Iversen et al.
Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6
J Urol
(2004)
F.H. Schröder et al.
Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846—a phase III study
J Urol
(2004)
F.H. Schroder et al.
Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer Protocol 30846 after 13 years of follow-up (a randomised controlled trial)
Eur Urol
(2009)
M.V. Pilepich et al.
Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long-term results of phase III RTOG 85-31
Int J Radiat Oncol Biol Phys
(2005)
T. Granfors et al.
Long-term followup of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone
J Urol
(2006)
J.W. Denham et al.
Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial
Lancet Oncol
(2005)

C.A. Lawton et al.

An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions

Int J Radiat Oncol Biol Phys

(2007)

A. Widmark 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)

M.V. Pilepich et al.

Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate

Int J Radiat Oncol Biol Phys

(2001)

J. Engel et al.

Survival benefit of radical prostatectomy in lymph node–positive patients with prostate cancer

Eur Urol

(2010)

U.E. Studer et al.

Using PSA to guide timing of androgen deprivation in patients with T0–4 N0–2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891)

Eur Urol

(2008)

P. Niehans

Prostata Krebs wie Paraprostata-Hypertrophie sind Folgen hormonaler Störungen die wir je früher je besser beeinflussen können

(1940)

B. Nair et al.

Early versus deferred androgen suppression in the treatment of advanced prostatic cancer

Cochrane Database Syst Rev

(2002)

S. Kumar et al.

Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer

Cochrane Database Syst Rev

(2006)

Cited by (70)

Reply to Ashwin Shinde, Richard Li, Arya Amini, and Scott Glaser's Letter to the Editor re: Liselotte M.S. Boevé Maarten C.C.M. Hulshof, André N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol 2019;75:410–8: Future Steps for Definitive Therapy in Metastatic Prostate Cancer: Lessons from the HORRAD Trial Until Randomised Controlled Trials Prove Different, Treat the Patient, Not His Imaging Results
2019, European Urology
Long-term outcomes of prostate cancer patients with lymph nodes metastasis after radical prostatectomy and pelvic lymph node dissection
2018, Progres en Urologie
Le but de notre étude a été d’évaluer la survie sans récidive biologique et d’en déterminer des facteurs prédictifs, des patients ayant un cancer de la prostate sans métastase ganglionnaire clinicoradiologique (cN0) lors du bilan préopératoire, ayant eu une prostatectomie totale avec curage ganglionnaire mettant en évidence une atteinte métastatique ganglionnaire (pN + ).
Étude multicentrique, rétrospective reprenant les dossiers des patients opérés entre janvier 2005 et décembre 2010 afin d’avoir au moins 5 ans de suivi. Nous avons analysé les survies sans récidive biologique et évalué des facteurs prédictifs de récidive biologique.
Au total, 30 patients ont été inclus dans l’étude. La durée de suivi moyen a été de 89,9 ± 27,4 mois. En postopératoire les patients ont eu une surveillance, une hormonothérapie adjuvante ou une radio-hormonothérapie adjuvante dans 13 %, 73 % et 14 % des cas respectivement. Durant le suivi, 50 % des patients ont eu une récidive biologique avec un délai d’apparition de la récidive de 38 ± 30 mois. La survie sans récidive biologique a été de 57 % à 5 ans et de 41 % à 10 ans. La présence de marges positives sur la pièce de prostatectomie (p = 0,0065) et de dépassement capsulaire au niveau ganglionnaire (p = 0,00021) ont été des facteurs prédictifs de récidive biologique.
La survie sans récidive biologique des patients ayant une atteinte ganglionnaire métastatique infraclinique après prostatectomie totale est satisfaisante et multifactorielle. De plus, notre étude a identifié les marges chirurgicales et l’extension extracapsulaire ganglionnaire comme des facteurs péjoratifs indépendants.
4.
The aim of this study was to evaluate biochemical recurrence-free survival (RFS) and to identify useful predictors of such survival in localized prostate cancer patients (cN0) and pelvic lymph node metastasis (pN + ) treated with radical prostatectomy and pelvic lymph node dissection.
This multicenter and retrospective study, assessed overall survival (OS), cancer specific survival (CSS) and biochemical recurrence-free survival (RFS), between January 2005 until December 2010 with 5 years of distance. We evaluated factors predicting long-term RFS in node positive prostate cancer patients.
Thus, 30 patients were included. Median follow-up was 89.9 ± 27.4 months. After surgery, patients were treated with surveillance (n = 4, 13.5%), adjuvant hormone therapy (n = 22, 73%) or combination of radio and hormone therapy, (n = 4, 13.5%). During the follow-up, 50% of patients had biochemical recurrence, with a mean time period of 38 ± 30 months. Five and 10-year RFS were 57% and 41% respectively. Extra lymph nodes extension (P = 0.00021) and pathological margin status (P = 0.0065) were independent predictors of 5-year RFS.
Biochemical RFS of patients treated with radical prostatectomy and subclinical lymph node metastatic disease is adequate and multifactorial. However, this study identifies pathological margin status and extra lymph node extension as independent factors of b RFS.
4.
Characteristics and national trends of patients receiving treatment of the primary tumor for metastatic prostate cancer
2017, Prostate International
Citation Excerpt :
Conversely, there was an increasing trend in the use of ADT for newly diagnosed metastatic patients. This result was surprising because of the emerging data on the potential value of locoregional treatment in node positive and metastatic disease.6–11 For example, in a review of the SEER (Surveillance, Epidemiology, and End Results)-Medicare database, Satkunasivam et al15 showed that radical prostatectomy and intensity-modulated radiation therapy (IMRT) were associated with decreased risk of prostate cancer-specific mortality at 6 months (52% reduction and 62% reduction, respectively) relative to no local therapy for patients with metastatic prostate cancer.
We sought to determine temporal trends in the receipt of prostatectomy or locoregional radiation to the prostate for patients with metastatic prostate cancer and to identify predictors of receipt of local treatment.
We identified 39,976 patients with metastatic prostate cancer diagnosed in 2004–2012 using the National Cancer Database (NCDB). We used logistic multivariable regression to determine trends in the receipt of prostate and/or pelvic radiation or radical prostatectomy after adjusting for demographic and clinical factors.
Patients with metastatic disease were less likely to receive locoregional treatment over time [7.88% in 2004 vs. 5.53% in 2012, adjusted odds ratio (AOR) = 0.97 per year, 95% confidence interval (CI) = 0.95–0.98; P < 0.001]. Cofactors associated with decreased likelihood for locoregional treatment included older age (AOR = 0.96 per year, 95% CI = 0.96–0.96, P < 0.001) and increased comorbidity level (1 comorbidity: AOR = 0.82, 95% CI = 0.73–0.93, P = 0.001; two or more comorbidities: AOR = 0.49, 95% CI = 0.39–0.61, P < 0.001). Decreasing utilization of both radiation and surgery of the primary site contributed to this trend. More specifically, patients with metastatic disease were less likely to receive radiation to the prostate and/or pelvis over time (5.9% in 2004 vs. 4.2% in 2012, AOR = 0.97 per year, 95% CI = 0.95–0.99, P < 0.001). Similarly, there was a trend toward decreased use of radical prostatectomy (2.17% in 2004 compared to 1.31% in 2012, AOR = 0.96 per year, 95% CI 0.93–0.99, P = 0.01).
Despite recent evidence of the possible benefit for locoregional treatment of prostate cancer in the setting of metastatic disease, rates of prostate radiation and radical prostatectomy among this population have actually declined over the 8-year period between 2004 and 2012, suggesting slow adoption of this novel treatment paradigm.
Reappraisal role of locoregional radiation therapy in metastatic cancers
2017, Bulletin du Cancer
Les innovations récentes dans le domaine de la cancérologie ont permis l’amélioration du pronostic de certains cancers y compris métastatiques avec une diminution de la mortalité. Les recommandations résument la prise en charge du cancer métastatique à la mise en place d’un traitement systémique ou de soins complémentaires et le traitement local n’intervient souvent qu’à visée symptomatique. Pourtant, dans la pratique courante, hors de l’« evidence based medicine », un traitement locorégional précoce (chirurgie ou radiothérapie) peut être proposé dans certains cas particuliers de cancers métastatiques d’emblée. Le but de la présente revue est de faire un état des lieux de la place de la radiothérapie de la tumeur primitive dans la maladie métastatique. Dans les cancers métastatiques du sein, de la prostate, du col de l’utérus, du côlon ou du cavum, un traitement local de la tumeur primitive incluant une radiothérapie locorégionale peut être discuté et décidé en RCP. Les essais en cours dans ces localisations devraient prochainement permettre de trancher sur le bénéfice du traitement locorégional. Il sera primordial de définir les critères précis qui permettront de sélectionner les patientes qui pourraient bénéficier de ce traitement.
Recent innovations in oncology area helped to improve the prognosis of certain cancers including metastatic ones with a decrease in mortality. Recommendations describe the treatment of metastatic cancer as systemic therapy or complementary care and the role of locoregional treatment in the treatment plan only occurs in a palliative context. Currently, in the clinical practice, out of “the evidence based medicine”, an early locoregional therapy (surgery or radiation therapy) can be proposed in several cases of metastatic cancers. The aim of the present review is to describe the role of the primary tumor radiation therapy in metastatic disease. In metastatic breast, prostate, cervix, rectal or nasopharyngeal cancers, locoregional treatment including radiation therapy can, in some cases, be discussed and decided in MDT. Ongoing clinical trials in these locations should soon precise the benefit of this locoregional treatment. It will also be important to define the specific criteria in order to select patients who could benefit from this treatment.
Management of Node-Positive and Oligometastatic Prostate Cancer
2017, Seminars in Radiation Oncology
Citation Excerpt :
In the past, RP was commonly avoided in patients with known node-positive prostate cancer as this was thought to represent systemic disease for which local treatment would be ineffective.13 This perception has shifted in recent years following the emergence of retrospective studies which suggested RP may improve outcomes in patients with nodal metastases (Table 3).14,15 The largest and most recent of these studies analyzed data from the Munich Cancer Registry, and compared OS among 938 clinically node-positive patients who received RP (n = 688) vs no treatment (n = 250).16
Historically, stage IV prostate cancer was considered incurable. Although node-positive and oligometastatic prostate cancers are both classified as stage IV, these likely represent distinct clinical groups, and some patients may be curable with aggressive multimodality treatments. There is a lack of randomized evidence, but retrospective studies suggest that radical prostatectomy or radiotherapy may improve survival in these patients. This is an area of great current research interest and prospective randomized trials are needed to help define the optimal treatments for these patients.
Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer Group-7
2016, European Urology
In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone.
To compare mortality rates in patients receiving ET alone versus ET + RAD.
From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70 Gy) at 3 mo.
PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models.
RAD added to ET.
With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29–39%) and 17% (95% confidence interval, 13–22%) in the ET and ET + RAD arms respectively (p < 0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age ≥65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity.
In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa.
Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis.

View all citing articles on Scopus

View full text

Review – Prostate CancerDoes Local Treatment of the Prostate in Advanced and/or Lymph Node Metastatic Disease Improve Efficacy of Androgen-Deprivation Therapy? A Systematic Review

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusions

Introduction

Section snippets

Evidence acquisition

Evidence synthesis

Conclusions

J Urol

Lancet Oncol

Eur Urol

Int J Radiat Oncol Biol Phys

J Urol

J Urol

Eur Urol

Int J Radiat Oncol Biol Phys

J Urol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Lancet

Int J Radiat Oncol Biol Phys

Eur Urol

Eur Urol

Prostata Krebs wie Paraprostata-Hypertrophie sind Folgen hormonaler Störungen die wir je früher je besser beeinflussen können

Early versus deferred androgen suppression in the treatment of advanced prostatic cancer

Cochrane Database Syst Rev

Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer

Cochrane Database Syst Rev

Review – Prostate Cancer
Does Local Treatment of the Prostate in Advanced and/or Lymph Node Metastatic Disease Improve Efficacy of Androgen-Deprivation Therapy? A Systematic Review