Locally advanced disease
(Locally advanced/high-risk prostate cancer—de novo presentation (clinical stage T3–4, and/or early-stage disease with PSA>20)
In these guidelines locally advanced/high risk prostate cancer is usually defined by clinical stage T3-4 and or early stage disease with PSA>20. However, to establish with certainty that it is locally advanced can be difficult and apart from clinical staging and the level of PSA, MRI scans can sometimes be of assistance as well as CT pelvis but both have low sensitivity. The presence of positive margins in the surgically resected specimen also points to the potential for locally advanced disease as does an early rise in the PSA, the rate of rise prior to localised treatment has also been suggested as a potential indicator of metastatic disease. However, in most cases it is the persistent rise in the PSA that has become a surrogate marker for advanced or metastatic disease after surgical resection of the prostate. Post radiotherapy if the PSA reaches its nadir and then starts to rise this is usually used as a surrogate marker of advanced disease. A measurable PSA after radical prostatectomy does not always indicate residual disease, as it could be due rarely to residual benign tissue. Biopsy of the prostatic bed can be performed to try to obtain tissue and /or monitoring of the rate of rise of the PSA in conjunction with knowledge of the Gleason score and presence of positive or negative margins may provide a means of determining whether the rise is due to a small remnant of benign tissue rather than metastatic disease.
Androgen Deprivation can be achieved in a number of ways. Testicular androgen production can be prevented by surgical castration, by chemical castration through the use of LHRH agonists, or by suppression of androgen production by oestrogens although because of undesirable cardiac side effects oral oestrogens are now rarely used. The other strategy is to use steroidal and non steroidal anti-androgens that compete with both testicular and andrenal androgens for the androgen receptor binding sites. These agents can be used singly and or in combination. It is important to note that there are some restrictions regarding the prescribing of these agents. LHRH agonists are available on the RPBS and anti androgens are only available on the PBS (authority) in combination with ADT. The non steroidal anti-androgens, bicalutamide and flutamide are approved only for use for stage D (metastatic) disease in combination with LHRH agonist therapy whereas the non-steroidal antiandrogen, nilutamide, is approved for use in combination with LHRH agonists or orchidectomy for the treatment of stage C (locally advanced) or D (metastatic prostate cancer). In contrast, the steroidal anti-androgen, cyproterone acetate is approved for the treatment of “advanced” prostate cancer.
Androgen deprivation therapy (ADT)
- What should be done for patients with locally advanced disease who are not suitable candidates for surgery or radiotherapy – primary androgen deprivation at diagnosis or wait until clinical progression (localized or metastatic) - Timing?
- What should be done for patients with locally advanced disease who are not suitable candidates for surgery or radiotherapy – primary androgen deprivation at diagnosis or wait until clinical progression (localized or metastatic)?
- Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects, specifically symptoms such as hot flushes, gynecomastia, liver function and gastrointestinal, effect on sexual function and cognitive function and possible long term side effects such as changes in body composition and metabolic syndrome for non metastatic disease?
- What is the incidence of osteoporosis and reduction in bone mineral density at 2, 5 and 10 years and what is the risk of osteoporotic bone fracture due to bilateral orchidectomy (or orchidectomy), LHRH agonist or long term androgen deficiency?
- What is the effect on Quality of Life as measured by validated questionnaires due to androgen ablation (deprivation or blockade) treatment?
- What is the efficacy of external beam radiotherapy techniques for locally advanced disease?
- What is the efficacy of external beam radiotherapy compared with other treatments for local control for locally advanced disease?
- What is the efficacy of radiation for locally advanced disease?
Radiotherapy and androgen deprivation therapy (ADT)
- Is there any survival advantage for androgen blockade (androgen ablation, deprivation) when used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer?
- Are cumulative treatment toxicities different when androgen blockade (androgen ablation, deprivation) is used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer in locally advanced disease?
Surgery plus androgen deprivation therapy
- 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?
- See Emerging therapies for ongoing trials in this area.
- See Bisphosphonates under castration-resistant prostate cancer for a discussion of a single trial of bisphosphonates for locally advanced disease.
Pathologic T3/T4 disease post radical surgery
- What is the efficacy of radiation post radical prostatectomy in patients with extra capsular extension, seminal vesicle involvement or positive surgical margins for locally advanced disease?
- Is there any survival advantage for androgen blockade (androgen ablation, deprivation) when used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced, node-positive prostate cancer?
- What is the efficacy of radiation for locally advanced node positive disease?