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Prostate Cancer

Chapter 07 - Hormonal Anti-Cancer Treatment in the Senior Cancer Patient

Prostate cancer is predominantly a disease of older men. In the era of screening with prostate-specific Antigen (PSA), most men are diagnosed with localised disease. Older men with prostate cancer usually die of other causes, with cardiovascular disease being the leading cause of death. In a subset of men with aggressive tumours and without major comorbidity, prostate cancer can progress rapidly to an advanced stage and cause death if not adequately treated.

The aim of androgen deprivation therapy (ADT) is to deprive prostate cancer of its predominant growth signal. Hormonal agents used in men with prostate cancer are as follows:

  • Gonadotropin-releasing hormone (GnRH) agonists (goserelin, buserelin, leuprolide) or antagonists (degarelix); alternative is bilateral orchiectomy
  • Nonsteroid anti-androgens: bicalutamide, nilutamide, flutamide, enzalutamide
  • Androgen synthesis inhibitors: ketoconazole, abiraterone acetate
  • Oestrogens: diethylstilbestrol (DES)
  • Miscellaneous: prednisone, dexamethasone

ADT in Men with Localised and Locally Advanced Prostate Cancer

Decisions regarding treatment should consider the patient’s tumour risk, treatment preferences, comorbidity, and life expectancy rather than chronologic age. Depending on the disease status and life expectancy, senior men with localised prostate cancer can be managed with the following treatment options:

  • Conservative (watchful waiting or active surveillance)
  • Brachytherapy
  • External beam radiotherapy
  • Radical prostatectomy

Each of these options can be used with or without ADT.

  • Randomised clinical trials have demonstrated improved prostate cancer– specific and overall survival from radiation therapy in combination with ADT as compared with radiation therapy alone in men with locally advanced prostate cancer. GnRH agonists should be started before or concurrent with radiotherapy and given for up to three years.
  • Use of ADT in combination with brachytherapy or radical prostatectomy has not demonstrated improved overall survival.
    • One small, randomised clinical trial demonstrated that adjuvant ADT after prostatectomy in men with node-positive disease and other high-risk features (e.g., positive margins, involvement of seminal vesicles) might be beneficial, but more evidence is required to support its use in this setting (Table 3).

Role of ADT in Various Clinical Settings of Prostate Cancer

Clinical settingRole of ADT
External radiotherapy for localised/locally advanced prostate cancerIn combination with external radiotherapy, ADT improves overall survival in men with locally advanced or intermediate and high-risk localised prostate cancer.
Brachytherapy for localised/locally advanced prostate cancerNeoadjuvant therapy with ADT has not been shown to improve overall survival
Radical Prostatectomy for localised/locally advanced prostate cancer

Neoadjuvant ADT does not improve overall survival. Adjuvant ADT in men with N0 disease does not improve overall survival.

Adjuvant ADT in men with N+ disease (and other adverse histopathologic factors such as positive margins, involvement of seminal vesicles) may improve overall survival, but further clinical trials are needed.

Biochemical (PSA only) recurrence in advanced prostate cancerNo proof from randomised clinical trials that ADT in men with biochemical recurrence is beneficial. However, some men with recurrence at high risk for cancer specific death (e.g., Gleason score 8-10, PSA doubling time ≤ 3 months) may benefit from immediate ADT.
Asymptomatic metastatic diseaseOptimal timing (immediate vs. deferred) of ADT remains controversial. In men who remain asymptomatic for a long time, ADT can be deferred.
Symptomatic prostate cancerADT should be given immediately to palliate symptoms and prolong overall survival.

Abbreviations: ADT, androgen deprivation therapy; N, lymph node; PSA, prostate-specific antigen.

Older men are less likely to receive radical treatment for prostate cancer as compared with younger men, but there is a general trend for increasing use of primary ADT. Data from randomised clinical trials and large observational studies show that primary ADT may improve cancer-specific mortality but does not improve overall survival in older men and may even be detrimental (Table above).

ADT in Advanced Prostate Cancer

To optimise treatment with ADT in men with advanced prostate cancer, the following two principles should be followed:

  • Monotherapy with a GnRH agonist can be recommended initially. A patient-based meta-analysis of more than 8,000 men demonstrated that addition of an anti-androgen [maximal androgen blockade (mAb)] did not improve overall survival significantly as compared with a GnRH agonist or bilateral orchidectomy alone. Monotherapy is also cheaper and less toxic.
  • Intermittent androgen blockade may be an option if the serum PSA falls to a low level. Results from several small randomised clinical trials support non-inferiority of intermittent ADT as compared with continuous ADT in men with advanced prostate cancer. Recently, results of two large randomised trials, which evaluated intermittent hormonal therapy were published. While non-inferiority of intermittent hormonal therapy was demonstrated in men who had PSA relapse after radical radiotherapy, non-inferiority was not confirmed in men with metastatic prostate cancer when compared to continuous hormonal therapy. Literature-based meta-analyses suggest that these strategies lead to equivalent survival in men with initial reduction in PSA to low levels. The main advantages of intermittent ADT are less time on a potentially toxic therapy, better quality of life, and decreased costs of treatment. However, most of the randomised clinical trials evaluated MAB, which cannot be considered standard of care, and future clinical trials should address intermittent versus continuous monotherapy.

Biochemical Relapse

Every third man after radical prostatectomy or radiotherapy experiences biochemical (PSA-only) relapse: only a subset of them will develop overt metastases, and an even smaller subset will die of prostate cancer. Radiation therapy is a potentially curative therapy for men with biochemical recurrence after radical prostatectomy if the source of increasing PSA is local recurrence. ADT is not curative, and there is no evidence from randomised clinical trials to support its use in men with biochemical recurrence. Results of a recent population-based outcome study shows no survival benefit of immediate ADT (started within 3 months of PSA relapse) when compared with deferred ADT initiation (started at least two years after PSA relapse or at clinical progression and short PSA doubling time) among prostate cancer patients with PSA-only relapse. It may be reasonable to consider treatment with ADT only in a subgroup of men with PSA relapse, who have a high risk for cancer-specific death (e.g., PSA doubling time ≤ 3 months, Gleason score 8–10, and short time from primary local treatment to the development of recurrence) (Table above).

Metastatic Prostate Cancer

Men with symptomatic metastatic prostate cancer should be treated with ADT. However, many men with metastases diagnosed by computed tomography or bone scan remain asymptomatic for a long time: it is reasonable to offer ADT to men with asymptomatic metastatic disease and rapidly rising PSA but not to those with slow progression.

Initially, more than 80% of patients respond to GnRH agonists or bilateral orchidectomy, but their disease will eventually progress after a median of 18 to 20 months. Three trials (GETUG-AFU-15, CHAARTED and STAMPEDE) have evaluated the upfront use of docetaxel in combination with ADT for men with metastatic prostate cancer. Two of these trials showed improved survival in the group given docetaxel. Most of the patients on these trials had high volume metastases at diagnosis and docetaxel should be recommended with ADT for fit men with a high burden of metastatic disease at time of diagnosis. ADT alone should remain standard for men with low burden disease and for those presenting with metastases several years after diagnosis of localised prostate cancer.

At progression, about one-third of men respond to the addition of an anti-androgen, and about 10 - 20% of those patients who respond and then progress will respond to withdrawal of the anti-androgen. Some men may respond to further hormonal therapies including dexamethasone, ketoconazole, or oestrogen (Table 3); their activity can be explained by (i) suppressed production of adrenal androgens (e.g., ketoconazole and dexamethasone) and (ii) direct anticancer effects (e.g., oestrogens and dexamethasone). However, none of these agents has demonstrated improvement in survival. In the light of new, more effective hormonal agents (i.e. abiraterone acetate and enzalutamide) further hormonal therapies such as dexamethasone, ketoconazole and oestrogen can be recommended only in countries where abiraterone acetate and enzalutamide are not available. Results of trials evaluating these agents in chemotherapy-naïve men with mCRPC also show delayed progression and improved survival. These agents can now be recommended at time of progression after initial ADT, whether or not this is given with docetaxel chemotherapy.

There is evidence that the androgen receptor remains a valid target in men with metastatic castrate-resistant prostate cancer (mCRPC). Abiraterone acetate and enzalutamide are effective new hormonal agents with a favourable benefit-risk profile. While abiraterone acetate blocks production of androgens in the adrenal gland and in metastases by the inhibition of the CYP17A1 Enzyme, enzalutamide potently blocks the androgen Receptor and signalling from it. In pivotal trials both agents have been shown to improve overall survival and quality of life of men with mCRPC who were previously treated with chemotherapy.

Side Effects of ADT

The risk of treatment with GnRH analogues needs to be assessed carefully in older men with prostate cancer. Well-recognised side effects include hot flashes, muscle loss, anaemia, sexual dysfunction, and gynecomastia, all of which can decrease quality of life. ADT can also increase risk for more serious and potentially life-threatening side effects such as metabolic syndrome, cardiovascular disease, and bone fractures. These toxicities can appear after a short period (e.g., months) of therapy with GnRH agonists and are particularly salient for a senior population. All men receiving ADT should receive calcium and vitamin D supplementation and should have evaluation of bone density periodically; annual treatment with zoledronic acid or treatment with denosumab every 6 months can prevent bone loss in those at risk. Health professionals should also evaluate cardiovascular risk when prescribing ADT to older men with prostate cancer, especially in settings without compelling evidence for its use (Table below).

Concurrent use of prednisone with abiraterone acetate decreases the risk for development of symptoms related to mineralocorticoid excess (hypokalaemia, hypertension and oedema). Some men experience severe fatigue with the newer hormonal agents, especially enzalutamide.

Major Side Effects of Androgen Deprivation Therapy

Androgen deprivation therapyMajor side effect
GnRH agonists
  • Male menopausal symptoms
  • Muscle loss
  • Bone loss/fractures
  • Loss of libido, impotence, gynecomastia
  • Metabolic syndrome, diabetes, cardiovascular disease
  • Anaemia
Anti-androgens (major drug-specific side effects)
  • Male menopausal symptoms
  • Gastrointestinal disturbance (bicalutamide, flutamide)
  • Gynaecomastia/mastodynia (bicalutamide)
  • Occular toxicity (nilutamide)
  • Pulmonary toxicity (nilutamide)
Miscellaneous
  • Cardiovascular disease (oestrogens)
  • Liver toxicity, gastrointestinal disturbance (ketoconazole)
  • Dermatologic toxicity (ketoconazole)
  • Diabetes (prednisone)
  • Hypertension (prednisone)

Abbreviation: GnRH, gonadotropin-releasing hormone.

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