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DOI: 10.1093/annonc/mdf644
Prostate cancer: management of advanced disease
J.-P. Droz, A. Fléchon & C. Terret
Centre Léon-Bérard, Department of Medical Oncology, Lyon, France
Introduction
Metastatic hormone-sensitive prostate cancer
Hormone deprivation is the major treatment at this stage of the
evolution.
Principles of first-line hormone suppression
The basis of first-line hormone suppression is castration by
either bilateral orchidectomy or LH-RH agonist administration. Three questions are important at this stage: what is the
role of complete anti-androgen blockade (CAB)? What is
the impact of hormone suppression on survival? What is the
optimal timing of hormone suppression?
Role of complete androgen blockade
Mechanism of action of therapeutics
Normal and malignant prostatic cells are sensitive to androgens.
There are two major sources of androgens: testicles, which
produce testosterone (95% of all androgens), and adrenal
glands (dehydroandrosterone, dehydroandrosterone sulphate
and androstenedione). Testicles and, to a lesser extent, adrenal
glands are under the control of the anterior lobe of the pituitary. Luteinizing hormone (LH) stimulates testosterone production by the testes. Luteinizing hormone secretion is under
the control of hypothalamic luteinizing hormone-releasing
hormone (LH-RH). Production of LH-RH is pulsatile. It is
reduced as a function of the serum testosterone level (feedback mechanism).
There are specific androgen receptors on normal and
malignant prostate cells which allow the internalization of
testosterone. Testosterone is then transformed into dihydrotestosterone (DHT), the active form of the hormone, which is
transported into the nucleus where it induces cell proliferation
(Figure 1). Drug and hormone manipulations have different
© 2002 European Society for Medical Oncology
Different trials were designed to study the impact of antiandrogen addition to castration. Only several trials included a
sufficient number of patients. One Intergroup trial in the USA,
which compared leuprolide with and without flutamide,
demonstrated a significantly longer progression-free survival
and median overall survival in the group of patients who
received CAB [3]. However, further large-scale trials failed
to demonstrate such a significant difference [4] even when
trials were designed to study good-prognosis patients. Metaanalysis was performed [5] but failed to demonstrate any
significant impact of CAB on survival. Consequently, CAB
cannot be recommended as standard treatment of metastatic
prostatic cancer.
Impact of androgen blockade on overall survival
A UK randomized trial has demonstrated a slight impact of
immediate versus deferred hormone suppression in advanced
prostate cancer [6]. The majority of patients had non-
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Advanced prostate cancer is an incurable disease. Treatment
objective is palliation only. The major observation is that prostate cancer is a hormone-sensitive tumour. Huggins and
Hodges [1] were the first to demonstrate that castration and
estrogen injection had therapeutic activity in men with metastatic prostate cancer. The most frequent metastatic sites in
prostate cancer are bone (85%), lymph nodes and further
visceral metastases (liver, central nervous system, lungs)
(45%) [2]. However, consequences of widespread metastases
are important: bone pain, nervous compression and haematological and metabolic consequences. All these conditions
must be taken into account in order to select the best treatment
options leading to a better quality of life for the patient. This
chapter focuses on the practical management of patients with
advanced disease; treatment evaluation criteria and new therapeutic approaches will be developed in another section of this
educational program.
mechanisms of action. The most simple androgen suppressor
is castration. The mechanism of action of other hormone treatments are shown in Table 1. LH-RH agonists act as orchidectomy, other drugs are peripheral inhibitors of androgens.
The major side effect of hormone suppression is loss of
potency. Other toxicities are shown in Table 1. However, one
particular side effect of LH-RH agonists, the flare syndrome,
must be prevented. At the beginning of treatment with LH-RH
agonists, a surge of LH, and a secondary increase of serum
testosterone level, is observed. This may induce an increase in
pain and, more importantly, tumour growth with bladder
retention, and spinal cord compression. It can be prevented by
anti-androgens administered 15 days before the first injection
of the LH-RH agonist.
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metastatic but locally advanced disease (55%) at the time of
randomization. Patients of the deferred treatment group were
treated when clinically significant progression occurred. All
events occurred more rapidly in the deferred treatment group:
progression from M0 to M1 disease, development of pain,
need of transuretheral resection for local progression, pathological fractures, spinal cord compression, ureteral obstruction and development of visceral metastases.
Early androgen blockade in patients with PSA level
increase after treatment of local disease
The rise of serum PSA levels after curative treatment (either
surgery or radiotherapy) is an indicator of infraclinical metastatic disease. Large randomized trials of immediate versus
delayed androgen blockade have been performed. No data are
yet available. Early treatment may not be recommended on the
basis of current knowledge.
Role of intermittent androgen blockade
The aim of this intermittent treatment is to delay the occurrence of androgen refractoriness and to decrease adverse
events of hormone suppression. Different phase II trials have
been published, phase III trials are on-going. This type of
treatment is still not standard [7].
Anti-androgen withdrawal syndrome
When patients are treated with the combination of LH-RH
agonist (or orchidectomy) and anti-androgens, it is observed
that anti-androgen withdrawal may induce some form of
benefit in almost 30% of patients, such as a decrease in pain or
a reduction of serum PSA levels [8]. This phenomenon seems
to be dependent on the occurrence of mutations on androgen
receptors and their ability to use anti-androgens as substrate. It
is thus recommended that anti-androgen therapy be stopped
when hormone resistance occurs after CAB.
Hormone resistance
Progression of prostate cancer to the hormone refractory
status is a universal phenomenon which is not well understood. It may be the result of an altered structure or expression
of androgen receptors or altered androgen receptor signalling
and interactions with other signal transduction pathways,
which possibly involve growth factor receptors [9].
Hormone refractoriness is clinically expressed in different
situations: increases in serum PSA levels, progression of
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Figure 1. Regulation of androgens. T, testosterone; 5αR, 5-α-reductase; DHT, dihydrotestosterone; DHEA, dehydroandrosterone.
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Table 1. Hormone treatments in prostate cancer: mechanisms of action and side effects
Drug
Mechanism of action
Side effects
Negative feedback of pulsatile secretion
of LH; initial LH surge
Flare-up syndrome, loss of potency, hot flushes
Competitive blockade of DHT to receptors
Diarrhoea, hepatotoxicity, flushing reactions,
hemeralopy, pulmonary fibrosis
LH-RH agonists
Leuprorelin
Goserelin
Buserelin
Triptorelin
Non-steroidal anti-androgens
Flutamide
Bicalutamide
Nilutamide
Steroidal anti-androgen
Inhibition of LH release; competitive blockade of
DHT to receptors
Estrogens
Diethyl-stilbestrol
Inhibition of LH release; inhibition of 5-α-reductase
activity; direct cytotoxic effect
Loss of potency; gynaecomastia; thromboembolism
Fosfestrol
DHT, dihydrotestosterone; LH, luteinizing hormone; LH-RH, luteinizing hormone-releasing hormone.
metastases, progression of pain and other symptoms while
hormone deprivation is continued.
pain for several days after treatment, whereas moderate
thrombocytopenia is observed in 5% of cases. This treatment
is indicated when diffuse pain is due to diffuse osseous metastases on bone scan.
Other therapeutic problems in the treatment
of advanced prostate cancer
Second- and third-line hormone therapy
The major observation is that no treatment has survival impact
at this disease stage. Only a few trials have studied the survival
impact of therapeutics, but none have shown any survival
benefit. Thus, treatment only has symptomatic (palliative)
impact. Symptoms are either local or diffuse. Treatment
options are based on the observation of symptoms. Symptoms
and therapeutic tools are summarized in Table 2.
Systemic treatment of metastatic hormone refractory prostate cancer is discussed elsewhere in this issue.
The most frequently used further hormone therapy lines are
anti-androgens, inhibitors of aromatase and estrogens [12].
Response rate is generally low at 10–20%. However, estrogens have a symptomatic effect, even in heavily pretreated
patients. Estramustine phosphate must be considered as a
chemotherapeutic agent, even though it is partly composed of
an estrogen molecule, because it acts as an inhibitor of microtubules. It is more active when combined with other cytotoxic
drugs.
Therapeutic tools
Clinical problems
Radiotherapy
Pain
Radiotherapy is active in the treatment of localized pain with a
response rate of 80%. It is administered in split courses
because its objective is only palliative.
Pain is the most frequent problem. The origin of pain is most
often central, sometimes neuropathic. Pharmacological treatment is specific for each mechanism. However, specific
treatments, mostly radiotherapy and radiopharmaceutics, are
indicated.
Radiopharmaceuticals
Two radiopharmaceuticals are used in the routine treatment of
diffuse metastatic bone pains: strontium [10] and samarium
[11]. They induce a 40% objective diminution of diffuse pains.
Toxicity is rare: patients may experience slightly increased
Spinal cord compression
Spinal bone involvement is observed in 80% of patients. However, spinal cord compression occurs is only 6% of patients.
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Cyproterone acetate
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Table 2. Symptoms in advanced disease prostate cancer and therapeutic tools
Symptoms
Therapeutic tools
Local symptoms
Local pain
Radiotherapy
Spinal cord compression
Surgery, radiotherapy
Urethral compression
Transurethral resection
Ureteral compression
Ureteral catheter
Cranial nerve compression
Radiotherapy
Diffuse symptoms
Diffuse pain
Hormone manipulation, chemotherapy, radiopharmaceuticals
Inflammatory symptoms
Fatigue, osteoporosis, denutrition
Corticosteroids, non-steroidal drugs
Urinary system compression
Consequences of long-term hormone suppression
Intracranial central nervous system involvement
Patients with hormone suppression develop osteoporosis. This
phenomenon has been well demonstrated in patients who
receive hormone suppression for local-stage prostate cancer
without bone metastasis. These patients have markers of
osteoporosis: osteocalcin pro-collagen, C-terminal propeptide
and collagen C-telopeptides. The estimated risk of fracture is
5% [14]. However, a majority of patients have osteoblastic
bone metastases. Thus, a combination of osteoblastic and
osteolytic metastases occurs in roughly 30% of patients.
Bisphosphonates have been studied in this patient population
in randomized trials. They support the use of bisphosphonates
that have been shown to improve pain control and quality
of life. A large National Cancer Institute Canada Protocol
comparing mitoxantrone plus prednisone with or without
intravenous clodronate for patients with symptomatic bone
metastases has been completed.
Intracranial involvement is classically infrequent, with only a
7% incidence in autopsy studies. Recent clinical experience
may suggest an increased incidence of these types of metastases. They are most commonly related to dural involvement.
The most frequent symptoms are jugular foramen syndrome
(pain of occiput, auricular region and shoulder), clivus syndrome (headache and VI to XII palsies), cavernous sinus
syndrome (III to VI palsies, ophthalmoplegia, facial numbness),
orbital syndrome (pain and exophtalmy), and mental neuropathy [15]. Several patients have true encephalopathy
syndrome. Diagnosis of dural involvement is often made by
MRI imaging. Radiotherapy is often active against symptoms.
However, all these symptoms must be differentiated from
cerebrovascular disorders which are frequent in this elderly
patient population.
Urinary system compression is a frequent symptom in patients
who have not received previous specific local treatment for
prostate cancer, but may also occur after prostate radiotherapy
and, rarely, after prostatectomy. It induces bladder retention
requiring transurethral resection. The major risk is urinary
incontinence. Sometimes the tumour involves the trigon and
spreads around the ureters. Unilateral or bilateral hydronephrosis is then observed, with a risk of renal failure. This
evolution generally requires the use of an intraureteral catheter.
Follow-up by urinary tract ultrasonography is proposed.
Haematological disorders
Surgery of bone metastases
As in other bone metastases, several orthopedic procedures
may be used: vertebrectomy with consolidation, intramedullar
nail, total hip replacement. The principal problems are linked
to the fact that bones are grossly involved and material may
not be well fixed. After surgery bone is generally irradiated in
split courses.
Pancytopenia (mostly anaemia and thrombocytopenia) may
be due to bone marrow involvement. Haematological diagnosis must be made because it may lead to active treatment by
chemotherapy and/or estrogens [16].
Intravascular coagulopathy is frequently observed. It
includes thrombocytopenia, decrease of coagulation factors
(II and VII), increase of D-dimers, of degradation products of
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Symptoms are local pain with characteristic metameric irradiations, dysesthesia in the same area and neurological central
nervous compression signs in the legs, and eventually paraplegia [13]. Treatment is difficult. The risk of spinal compression is evaluated by magnetic resonance imaging (MRI).
Radiotherapy is active in reducing pain, but may be insufficient to prevent spinal compression. Surgery is difficult because
the benefits of laminectomy are generally only short-lived
and more extensive surgery with consolidation procedures is
generally impossible due to multiple vertebral involvement.
Further prospective strategies must be developed.
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fibrin, and presence of schizocytes. It is often only a biological
phenomenon without clinical significance. When clinically
expressed (haemorrhage), it is treated by low-dose heparin,
fibrinogen and platelet transfusions, and specific treatment
(low-dose estrogens, high-dose estrogens, such as fosfestrol
phosphate, or chemotherapy). However prognosis is poor.
Inflammatory syndrome
Patients with advanced disease and multiple treatment lines
express inflammatory syndrome. At this end-stage, fever and
weight loss are frequent. Treatment is only symptomatic,
although corticosteroids and estrogens (diethylstilbestrol 1 mg)
may induce some palliative benefit.
The median survival of patients with metastatic prostate
cancer is 3 years, though it is only 1 year when the tumour
is hormone refractory. The number of possible problems is
great, but the major one is pain. The number of therapeutics is
also great. They have only palliative and symptomatic impact.
Early hormone suppression in patients with advanced disease
may have slight survival impact. Thus, a general scheme of
management can be proposed, based on several principles:
• Early hormone suppression is proposed in metastatic prostate cancer. Hormone suppression is achieved either by
castration or treatment with LH-RH agonists.
Table 3 summarizes the different problems encountered
and proposes a timetable of successive treatments. Several
questions still remain unsolved:
• Is simple androgen blockade or even anti-androgen alone
sufficient?
• What is the true usefulness of third-line hormone treatment? However, it seems that second-line treatment, being
either anti-androgen withdrawal or anti-androgen addition
depending on first line treatment, has some symptomatic
activity.
Table 3. Proposed chronology of treatment
Advanced disease: early first-line treatment
Androgen-blockade (castration or LH-RH agonist)
Hormone refractory disease: therapeutics are indicated on symptom occurrence
General treatment
Second-line hormone therapy
Specific treatment
Local therapeutics
Antiandrogens
Local radiotherapy
Aromatase inhibitors
Transurethral resection
Chemotherapy
Endoureteral catheter
Mitoxantrone prednisone
Spinal cord compression surgery
Trial
Orthopaedic surgery
Radiopharmaceutical
Corticosteroid plus estrogens
Drugs
Analgesic
Bisphosphonate
Calcium and vitamin D3
Treatment of intravascular
coagulopathy
Corticosteroids
Terminal care
LH-RH, luteinizing hormone-releasing hormone.
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Practical management of patients
• Powerful tools must be used to measure palliative impact:
pain and analgesic scales, quality of life evaluation. PSA
decrease may only be a surrogate of clinical response
evaluation.
• After first-line hormone suppression, indication of further
hormone therapy, chemotherapy and radiopharmaceutics is
based only on symptomatic progression. It is not based on
tumour progression as measured by PSA increase or metastasis evolution, because it is well established that, to date,
treatment has only a palliative effect.
• Management of local problems (urinary obstruction,
fracture, nerve compression) must be done depending on
the situation.
• Other general problems occur which require specific
management.
• Patients must be clearly informed of the palliative endpoints, therapeutic tools, current side effects and goals of
treatment. The strategy must be prospectively explained in
the early stages of treatment.
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• What are the maximal fields of radiotherapy which do not
impair the use of chemotherapy and radiopharmaceuticals?
• What is the best timing for chemotherapy and radiopharmaceuticals? The relative activity of different treatment sequences is unknown. Furthermore, these treatments
have not been compared together. It may also be possible
that chemotherapy induces more platelet toxicity after radiopharmaceutical administration.
• What should the timing of treatment (radiotherapy, surgery)
be in metastatic disease to the backbone?
• Should there be a particular management strategy for
elderly patients? There are arguments to think that comprehensive geriatric assessment may help to tailor more
actively specific treatments [17].
Acknowledgements
The authors thank Mrs Marie-France Mévélec for help in
the preparation of the material and Mrs Marie-Dominique
Reynaud for editing the manuscript.
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