Advanced prostate cancer

Summary of recommendations

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Summary of recommendations

This resource has been developed, reviewed or revised more than five years ago. It may no longer reflect current evidence or best practice.

For explanation of levels of evidence and grades for recommendations, see Levels of evidence and grades for recommendations below. You may also like to refer to the Appendix - Guideline development process

Psychosocial care

In men with prostate cancer, do interventions improve decision satisfaction, risk comprehension, knowledge about prostate cancer and understanding of their prognosis?

Recommendation Grade
Men with advanced prostate cancer should be offered education about their cancer, treatment options, and the benefits and disadvantages of available approaches, as well as strategies to manage treatment side effects at each stage in the progression of prostate cancer. A range of formats including written information, verbal instruction and multimedia could be considered. C

In men with prostate cancer, do psychological and cognitive interventions improve psychological adjustment?

Recommendation Grade
Men with advanced prostate cancer should be offered psychosocial interventions to enhance their adjustment.

Effective approaches include group-based cognitive behavioural interventions, nurse delivered education and support, sensory patient education, one-to-one peer support and group education and discussion (support groups).

However, psychosocial intervention research for prostate cancer has predominantly been undertaken with men with localised disease. Research addressing the unique psychosocial needs of men with advanced disease is needed.

B

In men with prostate cancer, do diet and lifestyle interventions improve quality of life?

Recommendation Grade
Men with advanced prostate cancer should be advised that resistance exercise and moderate to strenuous physical activity with expert supervision/support can improve quality of life and muscular fitness and reduce fatigue and the impact of fatigue on daily living. Unstable bone lesions and co-morbidities such as cardiovascular disease are exclusion criteria for studies on this topic and so are likely contraindications for this approach. D

In men with prostate cancer, do interventions improve sexual functioning?

Recommendation Grade
No recommendations are able to be made about effective ways to improve sexual

adjustment in men with advanced prostate cancer and their female or male partners. Research into effective interventions for men with advanced prostate cancer is needed.

D

In men with prostate cancer, do interventions alleviating partner distress improve quality of life?

Recommendation Grade
As yet there is insufficient evidence to strongly recommend a specific approach to reducing psychological distress and improving quality of life for the partners of men with advanced prostate cancer. However, group psycho-education may be of benefit. Research into effective interventions for the partners of men with advanced prostate cancer is urgently needed. D

What are the levels of psycho-social distress in men with advanced prostate cancer, including that related to PSA anxiety?

Recommendation Grade
Health professionals should be aware of risk factors for the development of anxiety and

depression and be prepared to treat appropriately.

B

Locally advanced disease

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?

Recommendation Grade
No strong recommendation can be made for the use of androgen deprivation therapy in locally advanced disease. However, there may be a modest benefit for immediate or primary androgen deprivation therapy for patients with locally advanced disease deemed not suitable for definitive local therapy. However, this has to be weighed against the impact of androgen deprivation therapy on quality of life. C

Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects for non metastatic disease?

Recommendation Grade
It is recommended that the prescriber take into account the following points when commencing ADT:
  • The use of non-steroidal anti-androgens as monotherapy may have fewer and less severe adverse events than medical or surgical castration but may still have a toxicity profile that impairs quality of life, and there is little to no efficacy data to support their use as monotherapy.
  • Extrapolating from evidence with metastatic disease (see Overt metastatic disease and/or loco-regional progressive disease), Combined androgen blockade (CAB) with an antiandrogen does increase the adverse event profile versus medical or surgical castration monotherapy and this needs to be weighed up against its marginal additional survival benefits seen in patients with metastatic disease.
  • When the unwanted effects of treatment are preferable to the unwanted effects of the tumour (e.g. prevent recurrence with increased overall survival in adjuvant setting), the side-effect profiles of the treatment options should be explained and strategies to minimise these effects should be considered with the patient.
B

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?

Recommendation Grade
Before commencing patients on androgen deprivation therapy, consider the likely duration of that treatment and the risk–benefit analysis for the indication for treatment, and take into account the effects on bone mineral density and risks of pathological fractures from osteoporosis. C

What is the effect on Quality of Life as measured by validated questionnaires due to androgen ablation (deprivation or blockade) treatment?

Recommendation Grade
Toxicities should be considered in the context of what is important to each individual patient, as for some patients impairment of sexual function may have a significant impact on their quality of life and overall adjustment, as well as affecting adversely those close to them. C

Radiotherapy

What is the efficacy of external beam radiotherapy techniques for locally advanced disease?

Recommendation Grade
When radiation therapy alone is used, limited field radiotherapy has similar efficacy and has less toxicity than whole pelvis and therefore is recommended. The role of whole pelvis radiation is yet to be defined.

Consideration should be given to dose escalation (74Gy or higher) if it can be delivered safely.

Patients with locally advanced prostate cancer should receive 3D conformal radiation to minimise toxicity.

C

What is the efficacy of external beam radiotherapy compared with other treatments for local control for locally advanced disease?

Recommendation Grade
Based on randomised trial evidence, it is not possible to quantify the degree of benefit

provided by radiotherapy alone for locally advanced prostate cancer. The role of surgery or hormonal therapy alone in this group of patients remains to be defined.

D
Radiation in addition to hormone therapy improves survival and is recommended. B

What is the efficacy of brachytherapy for locally advanced disease?

Recommendation Grade
3D conformal dose escalated external beam radiotherapy alone, or reduced dose external beam radiation treatment in combination with high dose-rate brachytherapy, are well recognised radical treatments for locally advanced disease. There is no randomised evidence to suggest superiority or to recommend one modality over the other. D

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?

Recommendation Grade
It is recommended that patients with locally advanced prostate cancer who are receiving

treatment with radical radiotherapy receive long-term androgen deprivation (at least two years).

B
Short-term neoadjuvant androgen deprivation therapy can be considered for patients with locally advanced prostate cancer. C
The optimal sequencing and duration of androgen deprivation in relation to radiotherapy is yet to be defined. C

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?

Recommendation Grade
Androgen deprivation therapy can be used in combination with radiotherapy without additional radiotherapy toxicities (urinary and gastrointestinal). Effect on sexual functioning has not been defined. C

Surgery

What is the evidence that surgery improves the outcomes in men with locally advanced disease?

Recommendation Grade
There is insufficient evidence to support the use of surgery in the management of advanced prostate cancer, with the possible exception of a transurethral resection of the prostate in men who are unable to void after androgen deprivation therapy. C

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?

Recommendation Grade
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

Pathologic T3/T4 disease post radical surgery (Patients with extra capsular extension, seminal vesicle involvement or positive surgical margins)

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?

Recommendation Grade
It is recommended that patients with extracapsular extension, seminal vesicle involvement or positive surgical margins receive post-operative EBRT within four months of surgery. The role of active surveillance and early salvage radiotherapy has not been defined. B

Node-positive 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?

Recommendation Grade
If radical radiotherapy is given to patients with node-positive disease it is reasonable to offer long-term androgen deprivation in addition to radiotherapy. D

What is the efficacy of radiation for locally advanced node positive disease?

Recommendation Grade
There is insufficient evidence to make a recommendation for the use of external beam

radiation as alternative or adjuvant to hormone therapies in node-positive patients.

Biochemical relapse

What should be done for patients with rising PSA levels and normal testosterone levels following definitive radiotherapy or radical prostatectomy?

Recommendation Grade
The optimal timing of androgen deprivation therapy in patients with biochemical relapse of disease without evidence of overt metastatic disease is not defined. Eligible patients should be informed about the current TROG Trial comparing early versus delayed hormonal therapy in this group.

Overt metastatic disease and/or loco-regional progressive disease

Androgen deprivation therapy

Is any one hormone therapy (androgen ablation) superior to another when given in the first line setting in terms of survival in metastatic disease?

Recommendation Grade
Patients with metastatic prostate cancer can be treated with either orchidectomy or LHRH agonist based on patient preference. Anti-androgen monotherapy should be avoided as the data indicate this is probably associated with a shorter overall survival. C

Is there any survival advantage for maximum androgen blockade (or combined hormone therapy) compared with single agent androgen blockade when used as first line therapy in metastatic disease?

Recommendation Grade
Patients with metastatic prostate cancer may be treated with a non-steroidal anti-androgen combined with androgen deprivation therapy as a continuing strategy (beyond the period of LHRH-induced surge [flare] of testosterone) if they are prepared to accept the greater likelihood of unwanted effects from combination therapy.

It is recommended that patients with high–volume disease or disease where urgent tumour debulking is required (eg impending spinal canal compression or urinary outflow obstruction) be commenced on combined androgen blockade to prevent flare reactions. This required period is approximately one month for an LHRH agonist and covers the time it takes for testosterone levels to reach a castrate state. Continuation of combined therapy beyond that period may be considered if the patient is prepared to accept the greater likelihood of unwanted side effects from combination therapy.

B

For patients with radiologically detectable but asymptomatic disease should hormone therapy be started immediately or should it be started at the onset of symptoms?

Recommendation Grade
Androgen deprivation therapy is indicated for metastatic prostate cancer. Immediate

therapy is warranted for symptomatic metastases. The evidence for immediate therapy for asymptomatic metastases is unclear, but it is definitely warranted if delay may result in complications (eg spinal cord compression from vertebral metastases).

C

Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects in metastatic disease?

Recommendation Grade
The benefits of androgen deprivation therapy in controlling a patient’s cancer outweigh the ADT adverse-event profile. However, given the clinically relevant and quality-of-life impairing litany of unwanted effects of ADT, the timing of commencement of ADT as a palliative treatment needs to be considered carefully. Assessment of liver function tests, risk of osteoporosis and bone density measurements as required is recommended. Baseline information on what is important to each individual patient should be ascertained (refer Complications and cumulative treatment toxicity). This will permit the commencement and nature of treatment to be tailored and allow an assessment of the cause of adverse effects if they emerge. The common side effects need to be discussed with the patient before commencing any ADT.


All patients taking anti-androgens should have their liver function tests monitored.

C

What is the effect on Quality of Life as measured by validated questionnaires due to androgen ablation (deprivation or blockade) treatment in metastatic disease?

Recommendation Grade
Toxicities in the context of what is important to each individual patient should be considered, as decrements in highly valued faculties for some patients may have a significant impact on the quality of life and overall adjustment of those individuals and those close to them. C

Is there a difference in survival for intermittent androgen deprivation compared to continuous androgen deprivation?

Recommendation Grade
No formal recommendation on intermittent or continuous androgen deprivation therapy can be made based on the lack of definitive data. However, it would appear that there may be a quality of life benefit. Intermittent androgen deprivation therapy can be considered for men who (i) achieve a good remission, (ii) are destined to be on ADT for a prolonged period, and (iii) are having intolerable side effects from long-term androgen deprivation. C

Radiotherapy

What is the effectiveness of local external beam radiotherapy (EBRT) in the palliation of uncomplicated bone pain?

Recommendation Grade
Radiotherapy is an effective and well-tolerated treatment for metastatic bone pain. A single dose of 8Gy is as effective as higher fractionated doses (eg 20–30Gy) in reducing bone pain. The higher incidence of re-treatment with lower-dose single fraction regimens should be considered as part of the decision-making process. C

What is the benefit of EBRT alone given for malignant spinal cord compression?

Recommendation Grade
For patients with malignant spinal cord compression the use of radiation is recommended. The optimal fractionation schedule of radiotherapy is unknown. D
Patients being treated with radiation for spinal cord compression should be given

dexamethasone at time of diagnosis.

B

What is the role of surgery in the treatment of malignant spinal cord compression?

Recommendation Grade
For highly selected patients with malignant spinal cord compression, vertebrectomy with

spinal stabilisation prior to radiotherapy should be considered. The role of decompression laminectomy prior to radiotherapy is unknown.

C

What is the efficacy of steroids for the treatment of malignant spinal cord compression?

Recommendation Grade
Patients being treated with radiotherapy for malignant spinal cord compression should also receive dexamethasone. C
The optimal dose of dexamethasone remains to be defined. D

Castration-resistant prostate cancer

Androgen deprivation therapy

Is any one hormone therapy (androgen ablation) superior to another when given in the first line setting in terms of survival in metastatic disease?

Recommendation Grade
There is a sequence of actions that should be followed when a patient is shown to have progressive cancer on androgen deprivation therapy.

First, confirm that the patient has a castrate level of testosterone if on an LHRH agonist therapy. If the patient is also on a nonsteroidal anti-androgen, this agent could be withdrawn and observed for the possibility of an anti-androgen withdrawal phenomenon.

It is reasonable to trial further hormone manipulations if the patient is asymptomatic or minimally symptomatic prior to use of chemotherapy (e.g. docetaxel).

C

Should LHRH agonist be continued when the patient is hormone refractory?

Recommendation Grade
There is insufficient evidence to make a recommendation as to whether a patient should continue LHRH agonist therapy once his disease has progressed while on androgen deprivation. D

Bisphosphonates

What is the evidence for the use of bisphosphonates in the prevention of skeletal related events?

Recommendation Grade
Zoledronic acid should be considered for the prevention of skeletal related events in men with asymptomatic or mildly symptomatic hormone resistant/castrate resistant metastatic prostate cancer.

Men as part of the informed consent process should be made aware that nine men will need to be treated for one to achieve a benefit and that there is a 5% risk of osteonecrosis of the jaw occurring during treatment.

Renal function needs to be monitored during treatment. Ideally treatment should be confined to men whose serum creatinine is less than 265umol/L at the time of starting treatment.

B

What is the evidence for the use of bisphosphonates in the treatment of bone pain?

Recommendation Grade
On the basis of the available evidence, bisphosphonates are not recommended for routine palliation of symptomatic bone disease in men, with hormone-resistant prostate cancer with a possible exception of zoledronic acid, where there is some evidence of a benefit in castrate-resistant men. C

Radioisotopes

What is the effectiveness of unsealed radioisotopes in the management of bone pain from prostate cancer?

Recommendation Grade
Unsealed radioisotopes may be considered for the management of multifocal bone pain

alongside other options of treatment in patients with hormone refractory prostate cancer.

C

Do unsealed radioisotopes improve survival in metastatic prostate cancer?

Recommendation Grade
The impact of unsealed radioisotopes on overall survival in men with castrate-resistant metastatic prostate cancer is undefined. The relative roles of unsealed radioisotopes and the newer chemotherapeutic agents (e.g. taxanes) and bisphosphonates have also not been defined. D

What is the evidence that quality of life is improved with unsealed radioisotopes in prostate cancer?

Recommendation Grade
It is not known what effect unsealed radioisotopes have on quality of life for men with metastatic prostate cancer. C

What is the toxicity of unsealed radioisotopes for treatment of metastatic prostate cancer?

Recommendation Grade
Unsealed radioisotopes alone may be associated with higher haematological adverse

events compared with supportive care or localised radiation, although overall these rates are low. Unsealed radioisotopes in combination with other treatments such as radiotherapy have higher rates of serious toxicity than radiotherapy alone. The toxicity of unsealed radioisotopes in combination with modern chemotherapy (taxanes) has not yet been defined and caution should be exercised if such combinations are considered.

C

Chemotherapy

Does cytotoxic chemotherapy give a survival benefit or any other benefits in terms of quality of life improvement, control of pain or other symptoms compared to patients not receiving chemotherapy or receiving different types of chemotherapy?

Recommendation Grade
Docetaxel in combination with prednisone is appropriate in the first line setting to improve survival, pain and quality of life in good performance patients with castrate-resistant metastatic prostate cancer. B
The combination of mitoxantrone and prednisolone also offers palliative benefit but no survival benefit compared to docetaxel. C

Palliative care

In men with advanced prostate cancer, what is the evidence that referral to specialist palliative care can assist in supporting a patient’s decision making and treatment planning processes?

Recommendation Grade
Men with metastatic prostate cancer should be referred for specialist palliative care or a coordinated palliative approach to assist in advance care planning. C

In men with advanced prostate cancer, what is the evidence that referral to specialist palliative care can assist with symptom control?

Recommendation Grade
Men with metastatic prostate cancer should be referred for interdisciplinary palliative care to assist in symptom control and in providing emotional, social and spiritual support. C



In men with advanced prostate cancer, what is the evidence that specialist palliative care can assist patients and families in providing effective end of life care?

Recommendation Grade
Men with metastatic prostate cancer and their families should be referred for a coordinated palliative approach to assist in providing effective end-of-life care. C

Complementary and alternative therapies

Complementary and alternative (unproven) therapies

Recommendation Grade
Health professionals should ask their patients about their use of CAM therapies in a supportive, understanding and non-judgmental way. D
Calcitriol in combination with docetaxel chemotherapy is not recommended on the basis of a large randomised trial which found excess mortality. A
Lycopene may benefit a small group of men with metastatic prostate cancer who have had no radiotherapy, no hormone therapy and who have had orchidectomy. In view of these findings, lycopene deserves to be further trialled. C
There is insufficient evidence to make any recommendations on dietary supplements in relation to quality of life, pain relief and toxicity. C

Socio-economic aspects of advanced prostate cancer

Socio-economic aspects of advanced prostate cancer

Recommendation Grade
Based on a lack of evidence from randomised trials or observational studies, it is not possible to determine whether socio-economic status is associated with differences in outcomes for men with locally advanced or metastatic prostate cancer. D

Levels of evidence and grades for recommendations

These guidelines are intended for use by all practitioners and health workers who require information about the management of patients with locally advanced and metastatic prostate cancer. They are wide-ranging in scope, covering prevention, screening, diagnosis and psychosocial matters, as well as the clinical aspects of surgery, radiotherapy and chemotherapy. The guidelines have been produced by a process of systematic literature review; critical appraisal and consultation encompassing all interested parties in Australia (see Appendix - Guideline development process)

The Summary of Recommendations table above provides a list of the evidence-based recommendations detailed in the text of each section. Table 1 below provides details on the highest level of evidence identified to support each recommendation (I-IV). The Summary of Recommendations table includes the grade for each recommendation (A-D) as shown in the table below. Individual levels of evidence can be found in the Evidence Summaries for each recommendation in each question.

Each recommendation was assigned a grade by the expert working group taking into account the volume, consistency, generalisability, applicability and clinical impact of the body of evidence supporting each recommendation.

Grade of recommendation Description
A Body of evidence can be trusted to guide practice
B Body of evidence can be trusted to guide practice in most situations
C Body of evidence provides some support for recommendation(s) but care should be taken in its application
D Body of evidence is weak and recommendation must be applied with caution

Table 1. Designations of levels of evidence according to type of research question (NHMRC, 2005)

Level Intervention
I A systematic review of level II studies
II A randomised controlled trial
III-1 A pseudo-randomised controlled trial (i.e. alternate allocation or some other method)
III-2 A comparative study with concurrent controls:
  • Non-randomised, experimental trial
  • Cohort study
  • Case-control study
  • Interrupted time series with a control group
III-3 A comparative study without concurrent controls:
  • Historical control study
  • Two or more single arm study
  • Interrupted time series without a parallel control group
IV Case series with either post-test or pre-test/post-test outcomes