For men with locally advanced prostate cancer, is there a role for peri-operative hormone therapy in the following situations: neoadjuvant setting, post-radical prostatectomy short duration, post-radical prostatectomy long duration?
The management of patients with locally advanced prostate cancer has been influenced by the introduction of androgen deprivation therapy (ADT). This review focuses on patients with locally advanced disease (ie pT3 or higher). Patients with T1 or T2 disease are dealt with in other guidelines.The inclusion of patients with pT3 or higher was due to the older literature studying patients based on volume of disease rather than histological grade. Moreover, patients with bulky (palpable disease) represent a different clinical paradigm. The role of adjuvant ADT with radiation therapy is discussed in the section Radiotherapy and androgen deprivation therapy.
The use of perioperative ADT in patients with locally advanced disease is discussed in the following clinical contexts:
- neoadjuvant setting
- post-radical prostatectomy short duration (<six months)
- post-radical prostatectomy long duration (>two years)
Fully resected pT3, T4, No/Nx disease
Most of the studies assessing the effects of neoadjuvant ADT focussed on patients with lower-stage disease and thus were excluded from this analysis. Those studies evaluating neoadjuvant ADT for prostatectomy patients with locally advanced disease predominantly reported changes in pathological stage. None was found that assessed survival. As a result, there are no available data on which to base a recommendation on neoadjuvant therapy for locally advanced disease. There is one continuing phase III trial of hormonal therapy plus docetaxel followed by surgery, versus surgery alone, for patients with high-risk disease (including patients with locally advanced disease (CALGB 90203 study).
There were no studies of short duration (six months or less) ADT as an adjuvant to prostatectomy for locally advanced disease. Two low-quality RCTs have examined the effects on survival of prolonged hormonal therapy as an adjuvant to prostatectomy or prostatectomy plus pelvic lymphadenectomy. One was a subgroup analysis and included some patients (4.3%) with radiologically- or biopsy-proven positive nodes. In the other study, patients also underwent a pelvic lymphadenectomy and only those who were pT3–4N0 were included in the study. In both studies the ADT was limited to antiandrogen alone. Neither study showed a survival advantage for anti-androgens alone as post-operative adjuvant therapy for patients with locally advanced disease. There were no data for medical or surgical castration as an adjuvant to surgery for fully resected primarily node-negative disease. As a result it is unknown whether the use of castration as adjuvant therapy for patients with marginpositive disease or similar high-risk features will confer a survival advantage. This is the subject of continuing clinical trials.
Microscopic fully resected node positive disease
There was a single RCT examining the effects of long-term adjuvant castration therapy for patients with microscopic fully resected node-positive disease. Unfortunately it was of medium quality as it was not blinded and it was closed early due to poor accrual. It therefore had small numbers and low power. There was a hazard ratio for survival of 3.0 with a median follow-up of 7.1 years18 and 2.14 with longer follow-up (median follow-up of 11.9 years, which was published in June 2006) favouring the long-term ADT arm. The notion of systemic therapy being beneficial is possibly consistent with the benefit seen in patients with high-risk disease treated with ADT and radiotherapy versus radiotherapy alone. The clinical impact of this data set is limited to patients with lymph node positive disease that has been resected. Only patients with pathological node-positive prostate cancer to undergo a lymph node dissection, which further supports performing the procedure in patients with high-risk prostate cancer.
It should be highlighted that the toxicity for patients on androgen deprivation is significant, with unwanted effects in terms of cardiovascular, genitourinary (impotency) systems as well as weight gain and gynaecomastia causing significant problems for a minority of patients (see Complications and cumulative treatment toxicity between different hormone therapy methods). The problem of hot flushes was rated as highly significant, affecting 59%. It should be noted that since this publication, a greater awareness of other untoward effects of ADT (such as bone substance loss and its consequences, the metabolic syndrome and cognitive problems) has occurred.
The translation of these data into practice is limited to patients with fully resected lymph node positive disease. It must therefore be emphasised that a lymph node dissection be undertaken. The use of ADT as adjuvant therapy for informed patients with lymph node positive disease in the Australian medical system is applicable, as the PBS requires patients to have ‘locally advanced (equivalent to stage C) disease’ (PBS wording).
The data from this one study (see below) for this selected group of patients support use of indefinite ADT. It is not known whether shorter durations (eg three years), such as those found to be beneficial with radiation, carry over to this setting.
Evidence summary and recommendations
| Neither of two RCTs for locally advanced disease (pT3–4No/Nx), neither of which showed a survival benefit for post-operative longterm anti-androgen therapy.
The effects of castration therapy as an adjuvant to prostatectomy have not been reported in an RCT.
|For fully resected node-positive disease there is evidence of overall survival advantage in one study that was closed early.||II|||
|For locally advanced prostate cancer, anti-androgens as an adjuvant monotherapy to radical prostatectomy are not recommended.||B|
|For node-positive disease androgen deprivation therapy (ADT) should be considered. For patients with fully resected node-positive disease (prostatectomy and lymphadenectomy), it is strongly recommended that patients be counselled on the overall survival benefit of ADT and weighed against the short- and long-term toxicities of androgen deprivation. It is further recommended that patients be counselled on the 'benefit’ of improved survival in relation to the ‘risk’ of therapy – namely the impact of ADT on quality of life.||C|
- McLeod DG, Iversen P, See WA, Morris T, Armstrong J, et al. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006 Feb;97(2):247-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16430622.
- Wirth MP, Weissbach L, Marx FJ, Heckl W, Jellinghaus W, Riedmiller H, 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 Mar;45(3):267-70; discussion 270 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15036669.
- Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999 Dec 9;341(24):1781-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10588962.
- Messing EM, Manola J, Yao J, Kiernan M, Crawford D, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Cooperative Oncology Group study EST 3886. Lancet Oncol 2006 Jun;7(6):472-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16750497.