Updated 18 August 2009
High Risk (must have any of the following):
- PSA >20 ng/mL
- Gleason >=8
- Stage T3a or greater
Treatment Options
Depending on the patient's age, general health, and disease-related parameters, a variety of therapeutic approaches may warrant consideration including combined radiation and androgen deprivation therapy, radical prostatectomy, radiotherapy alone, or androgen deprivation therapy alone.
Comparison of surgery and radiotherapy is hampered by a lack of randomised head-to-head trials, different definitions of high risk disease and biochemical recurrence, as well as variable addition of androgen deprivation therapy in reported series. Both are considered potential curative treatment options for appropriate cases in a multimodal therapeutic strategy to optimize outcomes in patients with high risk localized disease.
The combination of radiotherapy and androgen deprivation therapy contribute to incremental improvements in disease free and overall survival compared to either alone.
Multi-centre randomized trials have demonstrated improved overall survival, disease free survival, and local tumour control following external beam radiation therapy combined with concurrent and adjuvant androgen suppression of up to three years duration when compared with radiation therapy alone in men with high risk prostate cancer.
Neoadjuvant therapy has also shown benefit when given for several months prior to radiation. [Bolla et al: NEJM 1997:337/5;p295; Pilepich et al: J. Clin. Oncol.1997;15/3;p1013; Pilepich et al Urology, 1995,45:616-63; RTOG 92-02 ASCO 2000].
Three years of androgen deprivation therapy has been shown to be more effective than six months of androgen deprivation therapy with respect to biochemical and a modest improvement in overall survival (Bolla et al, NEJM 2009:360; p2516); however, the optimal duration of androgen ablation continues to be defined. The use and duration of use of androgen ablation prior to the start of radiotherapy (ie neoadjuvant component) is also evolving, but prospective trials suggest that up to eight months of neoadjuvant androgen ablation is an option (Crook et al. Int J Rad Onc Biol Phys: 73(2); 327-333. Denham et al. Lancet Oncology:2005; 6(11);841-850.)
The optimum duration of adjuvant androgen deprivation therapy and the trade-off between toxicity and potential benefit depends on disease and patient factors and will be individualized in consultation with the oncologist. The combination of radiotherapy with non-steroidal anti-androgen based mono-hormonal therapy compared to non-steroidal anti-androgen therapy alone, improved the ten year overall survival by 10% in one large study (Widemark et al: Lancet 2009: 373;301-308).
Patients who are candidates for curative radiation treatment for localized prostate cancer, but who have "high-intermediate" or high-risk criteria may also be offered neoadjuvant androgen deprivation therapy for up to eight months duration, to be followed by concurrent/adjuvant therapy (giving a total duration of up to three years), in addition to their definitive radiotherapy. In addition, selected patients with bulky benign prostate glands containing low-risk tumours may require neoadjuvant therapy to reduce the volume of tissue irradiated and so reduce toxicity.
The use of neoadjuvant androgen deprivation therapy in the 'low-risk' patient should be avoided because the patient will be exposed to toxicity of androgen deprivation treatment with evidence of increased morbidity and mortality from androgen deprivation therapy in some studies. Generally, the survival benefit seen in randomized trials has been limited to those with high risk cancer, and benefits with intermediate risk patients are limited to biochemical control advantages.
Several randomized trials have demonstrated a disease free survival benefit to dose escalation to doses 74 Gy compared to lower doses (Int J Rad Onc Biol Phys 72(4): pg 980, Dearnaley, Lancet Oncology 2007, Kuban, Int J Rad Onc Biol Phys 2007). Selected patients may also be offered total androgen blockade in the neoadjuvant period. The use of image guided and or intensity modulated radiotherapy may improve outcomes with radiotherapy in terms of toxicity or disease control. The role of brachytherapy as a component of dose escalation for high risk prostate cancer patients is evolving. High risk prostate cancer patients may be eligible for clinical trials investigating the role of radiation dose escalation (eg ASCEND RT), or the use of neoadjuvant chemotherapy prior to radiotherapy (eg DART), or prior to surgery (eg NCIC PRC.3/CALGB 90203).
Referring doctors are asked not to institute androgen suppression therapy prior to consultation with a radiation oncologist or the treating urologist because:
- the extent of the disease and the appropriate size of potential radiation fields may become difficult to judge after castration-induced tumour regression; and
- this may affect a patient's eligibility for proposed and ongoing clinical trials.
The role of radical prostatectomy in the context of potential multimodal therapy for high risk clinically localized prostate cancer is supported by accumulating evidence.
In a series of 240 patients with high risk localized prostate cancer who underwent radical prostatectomy (with androgen deprivation therapy in 71%) at Vancouver General Hospital, PSA recurrence (defined as >0.4 µg/L) was 31%. Those patients with only one adverse factor had good PSA control of ~60% at five years, whereas those with multiple adverse factors had a brief time to relapse of only ~ two years.
A series of 842 patients from the Mayo Clinic with clinical T3 disease and a median follow-up of > ten years after prostatectomy reported biochemical progression-free survival 43% at ten years; 78% received ADT and 41% radiotherapy at some point after their surgery (Ward BJU 2005).
Similar results are reported from a Belgian surgical series of 235 clinical T3a CAP patients, reported biochemical PFS of 51.5% at ten years (Hsu Eur Urol 2007), although 56% of these patients had either adjuvant or salvage RT and/or ADT.
Post Radical Prostatectomy Adjuvant Radiotherapy
Post-radical prostatectomy radiotherapy is recommended for patients with pathologic T3 (ie extracapsular extension or seminal vesicle invasion) or margin positive disease who are considered at high risk of local recurrence.
Three randomized trials have demonstrated a reduction of the risk of recurrence after early adjuvant radiotherapy for men with pT3 cancer or positive margins after a radical prostatectomy, compared to no early adjuvant radiotherapy (Wigel et al, JCO 2009: 27(8); pg2924. Thompson et al, J Urol. 2009: 181: pg956. Van Der Kwast, JCO 2007: 25(27): pg4178), and one study has showed a 10% increase in ten year overall survival.
As a result, early adjuvant radiotherapy is considered the standard of care for patients with these risk factors. Subgroup analysis from some of the studies have suggested the benefit is restricted to those patients with positive margins (Van Der Kwast, JCO 2007: 25(27): pg 4178.), and the three randomized trials predate the use of routine PSA testing in follow-up, therefore ongoing randomized trials are testing the hypothesis that salvage RT at time of first PSA relapse will provide a similar outcome to adjuvant RT.
We recommend referral to the BC Cancer Agency for consultation with a radiation oncologist for patients with pT3 disease or positive margins, prior to any adjuvant hormonal treatment and early (within three months of surgery) in the postoperative period. Observation alone may be appropriate in some candidates. Patients may be offered enrolment in the RADICALS trial, which is an international phase III study testing whether early adjuvant radiotherapy is more effective than radiotherapy delayed until PSA is rising. This study also randomizes patients to the addition of androgen deprivation therapy for various durations for patients considered to need radiotherapy.
Other clinical trials may be available at the time of PSA relapse after prostatectomy (eg Tax 3503, which is examining the role of Taxotere in addition to salvage androgen ablation). There is a list of Open Clinical Trials on the Genitourinary page.
T4 N0
Treatment needs to be individualized and may involve radical or palliative radiotherapy and/or early or delayed androgen deprivation therapy. Radiotherapy in addition to androgen deprivation therapy is likely to improve local control and may confer additional metastasis free and overall survival benefit for some patients (Widemark et al: Lancet 2009: 373;301-308).
Stage Any T, N1-3
Treatment Options
- Early or delayed androgen deprivation therapy, and/or
The general trend is towards immediate androgen withdrawal therapy at the time of diagnosis of metastatic disease rather than waiting for symptomatic progression.
Increasing and evolving evidence suggests that treatment should commence at the time of diagnosis of locally advanced or metastatic disease. However, some delay of treatment in sexually active, asymptomatic men is a reasonable alternative, and the potentially adverse effect on quality of life should be taken into account (JCO 2006: 24(18S);4513, JCO 2007: 25(18S); 5015).
The use of intermittent androgen ablation has been examined in several randomized trials and initial results suggest that survival rates are not compromised with intermittent androgen ablation.
