Prostate cancer: management of advanced disease
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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 mechanisms of action. The most simple androgen suppressor
is castration. The mechanism of action of other hormone treat-
Advanced prostate cancer is an incurable disease. Treatment
ments are shown in Table 1. LH-RH agonists act as orchid-
objective is palliation only. The major observation is that pro-
ectomy, other drugs are peripheral inhibitors of androgens.
state cancer is a hormone-sensitive tumour. Huggins and
The major side effect of hormone suppression is loss of
Hodges [1] were the first to demonstrate that castration and
potency. Other toxicities are shown in Table 1. However, one
estrogen injection had therapeutic activity in men with meta-
particular side effect of LH-RH agonists, the flare syndrome,
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static prostate cancer. The most frequent metastatic sites in
must be prevented. At the beginning of treatment with LH-RH
prostate cancer are bone (85%), lymph nodes and further
agonists, a surge of LH, and a secondary increase of serum
visceral metastases (liver, central nervous system, lungs)
testosterone level, is observed. This may induce an increase in
(45%) [2]. However, consequences of widespread metastases
pain and, more importantly, tumour growth with bladder
are important: bone pain, nervous compression and haemato-
retention, and spinal cord compression. It can be prevented by
logical and metabolic consequences. All these conditions
anti-androgens administered 15 days before the first injection
must be taken into account in order to select the best treatment
of the LH-RH agonist.
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 thera- Principles of first-line hormone suppression
peutic approaches will be developed in another section of this The basis of first-line hormone suppression is castration by
educational program. either bilateral orchidectomy or LH-RH agonist administra-
tion. Three questions are important at this stage: what is the
role of complete anti-androgen blockade (CAB)? What is
Metastatic hormone-sensitive prostate cancer
the impact of hormone suppression on survival? What is the
Hormone deprivation is the major treatment at this stage of the optimal timing of hormone suppression?
evolution.
Role of complete androgen blockade
Mechanism of action of therapeutics
Different trials were designed to study the impact of anti-
Normal and malignant prostatic cells are sensitive to androgens. androgen addition to castration. Only several trials included a
There are two major sources of androgens: testicles, which sufficient number of patients. One Intergroup trial in the USA,
produce testosterone (95% of all androgens), and adrenal which compared leuprolide with and without flutamide,
glands (dehydroandrosterone, dehydroandrosterone sulphate demonstrated a significantly longer progression-free survival
and androstenedione). Testicles and, to a lesser extent, adrenal and median overall survival in the group of patients who
glands are under the control of the anterior lobe of the pituit- received CAB [3]. However, further large-scale trials failed
ary. Luteinizing hormone (LH) stimulates testosterone pro- to demonstrate such a significant difference [4] even when
duction by the testes. Luteinizing hormone secretion is under trials were designed to study good-prognosis patients. Meta-
the control of hypothalamic luteinizing hormone-releasing analysis was performed [5] but failed to demonstrate any
hormone (LH-RH). Production of LH-RH is pulsatile. It is significant impact of CAB on survival. Consequently, CAB
reduced as a function of the serum testosterone level (feed- cannot be recommended as standard treatment of metastatic
back mechanism). prostatic cancer.
There are specific androgen receptors on normal and
malignant prostate cells which allow the internalization of
Impact of androgen blockade on overall survival
testosterone. Testosterone is then transformed into dihydro-
testosterone (DHT), the active form of the hormone, which is A UK randomized trial has demonstrated a slight impact of
transported into the nucleus where it induces cell proliferation immediate versus deferred hormone suppression in advanced
(Figure 1). Drug and hormone manipulations have different prostate cancer [6]. The majority of patients had non-
© 2002 European Society for Medical Oncology90
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Figure 1. Regulation of androgens. T, testosterone; 5αR, 5-α-reductase; DHT, dihydrotestosterone; DHEA, dehydroandrosterone.
metastatic but locally advanced disease (55%) at the time of been published, phase III trials are on-going. This type of
randomization. Patients of the deferred treatment group were treatment is still not standard [7].
treated when clinically significant progression occurred. All
events occurred more rapidly in the deferred treatment group: Anti-androgen withdrawal syndrome
progression from M0 to M1 disease, development of pain,
When patients are treated with the combination of LH-RH
need of transuretheral resection for local progression, patho-
agonist (or orchidectomy) and anti-androgens, it is observed
logical fractures, spinal cord compression, ureteral obstruc-
that anti-androgen withdrawal may induce some form of
tion and development of visceral metastases.
benefit in almost 30% of patients, such as a decrease in pain or
a reduction of serum PSA levels [8]. This phenomenon seems
Early androgen blockade in patients with PSA level to be dependent on the occurrence of mutations on androgen
increase after treatment of local disease receptors and their ability to use anti-androgens as substrate. It
is thus recommended that anti-androgen therapy be stopped
The rise of serum PSA levels after curative treatment (either
when hormone resistance occurs after CAB.
surgery or radiotherapy) is an indicator of infraclinical meta-
static disease. Large randomized trials of immediate versus
delayed androgen blockade have been performed. No data are Hormone resistance
yet available. Early treatment may not be recommended on the Progression of prostate cancer to the hormone refractory
basis of current knowledge. status is a universal phenomenon which is not well under-
stood. It may be the result of an altered structure or expression
Role of intermittent androgen blockade of androgen receptors or altered androgen receptor signalling
and interactions with other signal transduction pathways,
The aim of this intermittent treatment is to delay the occur- which possibly involve growth factor receptors [9].
rence of androgen refractoriness and to decrease adverse Hormone refractoriness is clinically expressed in different
events of hormone suppression. Different phase II trials have situations: increases in serum PSA levels, progression of91
Table 1. Hormone treatments in prostate cancer: mechanisms of action and side effects
Drug Mechanism of action Side effects
LH-RH agonists
Leuprorelin Negative feedback of pulsatile secretion Flare-up syndrome, loss of potency, hot flushes
of LH; initial LH surge
Goserelin
Buserelin
Triptorelin
Non-steroidal anti-androgens
Flutamide Competitive blockade of DHT to receptors Diarrhoea, hepatotoxicity, flushing reactions,
hemeralopy, pulmonary fibrosis
Bicalutamide
Nilutamide
Steroidal anti-androgen
Cyproterone acetate Inhibition of LH release; competitive blockade of
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DHT to receptors
Estrogens
Diethyl-stilbestrol Inhibition of LH release; inhibition of 5-α-reductase Loss of potency; gynaecomastia; thromboembolism
activity; direct cytotoxic effect
Fosfestrol
DHT, dihydrotestosterone; LH, luteinizing hormone; LH-RH, luteinizing hormone-releasing hormone.
metastases, progression of pain and other symptoms while pain for several days after treatment, whereas moderate
hormone deprivation is continued. thrombocytopenia is observed in 5% of cases. This treatment
is indicated when diffuse pain is due to diffuse osseous meta-
stases 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 The most frequently used further hormone therapy lines are
at this disease stage. Only a few trials have studied the survival anti-androgens, inhibitors of aromatase and estrogens [12].
impact of therapeutics, but none have shown any survival Response rate is generally low at 10–20%. However, estro-
benefit. Thus, treatment only has symptomatic (palliative) gens have a symptomatic effect, even in heavily pretreated
impact. Symptoms are either local or diffuse. Treatment patients. Estramustine phosphate must be considered as a
options are based on the observation of symptoms. Symptoms chemotherapeutic agent, even though it is partly composed of
and therapeutic tools are summarized in Table 2. an estrogen molecule, because it acts as an inhibitor of micro-
Systemic treatment of metastatic hormone refractory pros- tubules. It is more active when combined with other cytotoxic
tate cancer is discussed elsewhere in this issue. drugs.
Therapeutic tools Clinical problems
Radiotherapy Pain
Radiotherapy is active in the treatment of localized pain with a Pain is the most frequent problem. The origin of pain is most
response rate of 80%. It is administered in split courses often central, sometimes neuropathic. Pharmacological treat-
because its objective is only palliative. ment is specific for each mechanism. However, specific
treatments, mostly radiotherapy and radiopharmaceutics, are
Radiopharmaceuticals indicated.
Two radiopharmaceuticals are used in the routine treatment of
Spinal cord compression
diffuse metastatic bone pains: strontium [10] and samarium
[11]. They induce a 40% objective diminution of diffuse pains. Spinal bone involvement is observed in 80% of patients. How-
Toxicity is rare: patients may experience slightly increased ever, spinal cord compression occurs is only 6% of patients.92
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
Symptoms are local pain with characteristic metameric irradi- Urinary system compression
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ations, dysesthesia in the same area and neurological central
Urinary system compression is a frequent symptom in patients
nervous compression signs in the legs, and eventually para-
who have not received previous specific local treatment for
plegia [13]. Treatment is difficult. The risk of spinal compres-
prostate cancer, but may also occur after prostate radiotherapy
sion is evaluated by magnetic resonance imaging (MRI).
and, rarely, after prostatectomy. It induces bladder retention
Radiotherapy is active in reducing pain, but may be insuffi-
requiring transurethral resection. The major risk is urinary
cient to prevent spinal compression. Surgery is difficult because
incontinence. Sometimes the tumour involves the trigon and
the benefits of laminectomy are generally only short-lived
spreads around the ureters. Unilateral or bilateral hydro-
and more extensive surgery with consolidation procedures is
nephrosis is then observed, with a risk of renal failure. This
generally impossible due to multiple vertebral involvement.
evolution generally requires the use of an intraureteral catheter.
Further prospective strategies must be developed. Follow-up by urinary tract ultrasonography is proposed.
Consequences of long-term hormone suppression Intracranial central nervous system involvement
Patients with hormone suppression develop osteoporosis. This Intracranial involvement is classically infrequent, with only a
phenomenon has been well demonstrated in patients who 7% incidence in autopsy studies. Recent clinical experience
receive hormone suppression for local-stage prostate cancer may suggest an increased incidence of these types of meta-
without bone metastasis. These patients have markers of stases. They are most commonly related to dural involvement.
osteoporosis: osteocalcin pro-collagen, C-terminal propeptide The most frequent symptoms are jugular foramen syndrome
and collagen C-telopeptides. The estimated risk of fracture is (pain of occiput, auricular region and shoulder), clivus syn-
5% [14]. However, a majority of patients have osteoblastic drome (headache and VI to XII palsies), cavernous sinus
bone metastases. Thus, a combination of osteoblastic and syndrome (III to VI palsies, ophthalmoplegia, facial numbness),
osteolytic metastases occurs in roughly 30% of patients. orbital syndrome (pain and exophtalmy), and mental neuro-
Bisphosphonates have been studied in this patient population pathy [15]. Several patients have true encephalopathy
in randomized trials. They support the use of bisphosphonates syndrome. Diagnosis of dural involvement is often made by
that have been shown to improve pain control and quality MRI imaging. Radiotherapy is often active against symptoms.
of life. A large National Cancer Institute Canada Protocol However, all these symptoms must be differentiated from
comparing mitoxantrone plus prednisone with or without cerebrovascular disorders which are frequent in this elderly
intravenous clodronate for patients with symptomatic bone patient population.
metastases has been completed.
Haematological disorders
Surgery of bone metastases
Pancytopenia (mostly anaemia and thrombocytopenia) may
As in other bone metastases, several orthopedic procedures be due to bone marrow involvement. Haematological diagno-
may be used: vertebrectomy with consolidation, intramedullar sis must be made because it may lead to active treatment by
nail, total hip replacement. The principal problems are linked chemotherapy and/or estrogens [16].
to the fact that bones are grossly involved and material may Intravascular coagulopathy is frequently observed. It
not be well fixed. After surgery bone is generally irradiated in includes thrombocytopenia, decrease of coagulation factors
split courses. (II and VII), increase of D-dimers, of degradation products of93
fibrin, and presence of schizocytes. It is often only a biological • Powerful tools must be used to measure palliative impact:
phenomenon without clinical significance. When clinically pain and analgesic scales, quality of life evaluation. PSA
expressed (haemorrhage), it is treated by low-dose heparin, decrease may only be a surrogate of clinical response
fibrinogen and platelet transfusions, and specific treatment evaluation.
(low-dose estrogens, high-dose estrogens, such as fosfestrol • After first-line hormone suppression, indication of further
phosphate, or chemotherapy). However prognosis is poor. hormone therapy, chemotherapy and radiopharmaceutics is
based only on symptomatic progression. It is not based on
tumour progression as measured by PSA increase or meta-
Inflammatory syndrome stasis evolution, because it is well established that, to date,
Patients with advanced disease and multiple treatment lines treatment has only a palliative effect.
express inflammatory syndrome. At this end-stage, fever and • Management of local problems (urinary obstruction,
weight loss are frequent. Treatment is only symptomatic, fracture, nerve compression) must be done depending on
although corticosteroids and estrogens (diethylstilbestrol 1 mg) the situation.
• Other general problems occur which require specific
may induce some palliative benefit.
management.
• Patients must be clearly informed of the palliative end-
Practical management of patients points, therapeutic tools, current side effects and goals of
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treatment. The strategy must be prospectively explained in
The median survival of patients with metastatic prostate the early stages of treatment.
cancer is 3 years, though it is only 1 year when the tumour
Table 3 summarizes the different problems encountered
is hormone refractory. The number of possible problems is
and proposes a timetable of successive treatments. Several
great, but the major one is pain. The number of therapeutics is
questions still remain unsolved:
also great. They have only palliative and symptomatic impact.
Early hormone suppression in patients with advanced disease • Is simple androgen blockade or even anti-androgen alone
may have slight survival impact. Thus, a general scheme of sufficient?
management can be proposed, based on several principles: • What is the true usefulness of third-line hormone treat-
ment? However, it seems that second-line treatment, being
• Early hormone suppression is proposed in metastatic pro- either anti-androgen withdrawal or anti-androgen addition
state cancer. Hormone suppression is achieved either by depending on first line treatment, has some symptomatic
castration or treatment with LH-RH agonists. 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 Specific treatment
Second-line hormone therapy Local therapeutics
Antiandrogens Local radiotherapy
Aromatase inhibitors Transurethral resection
Chemotherapy Endoureteral catheter
Mitoxantrone prednisone Spinal cord compression surgery
Trial Orthopaedic surgery
Radiopharmaceutical Drugs
Corticosteroid plus estrogens Analgesic
Bisphosphonate
Calcium and vitamin D3
Treatment of intravascular
coagulopathy
Corticosteroids
Terminal care
LH-RH, luteinizing hormone-releasing hormone.94
• What are the maximal fields of radiotherapy which do not 4. Eisenberger MA, Blumenstein BA, Crawford ED et al. Bilateral
impair the use of chemotherapy and radiopharmaceuticals? orchiectomy with or without flutamide for metastatic prostate cancer.
• What is the best timing for chemotherapy and radio- N Engl J Med 1998; 339: 1036–1042.
pharmaceuticals? The relative activity of different treat- 5. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen
ment sequences is unknown. Furthermore, these treatments blockade in advanced prostate cancer: an overview of 22 randomised
trials with 3283 deaths in 5710 patients. Lancet 1995; 346: 265–269.
have not been compared together. It may also be possible
6. The Medical Research Council Prostate Cancer Working Party
that chemotherapy induces more platelet toxicity after radio-
Investigators Group. Immediate versus deferred treatment for
pharmaceutical administration.
advanced prostatic cancer: initial results of the Medical Research
• What should the timing of treatment (radiotherapy, surgery) Council Trial. Br J Urol 1997; 79: 235–246.
be in metastatic disease to the backbone? 7. Dawson NA. Intermittent androgen deprivation. Curr Oncol Rep
• Should there be a particular management strategy for 2000; 2: 409–416.
elderly patients? There are arguments to think that com- 8. Scher HI, Zhang ZF, Nanus D, Kelly WK. Hormone and antihormone
prehensive geriatric assessment may help to tailor more withdrawal: implications for the management of androgen-
actively specific treatments [17]. independent prostate cancer. Urology 1996; 47: 61–69.
However, it is recommended that patients with metastatic 9. Mitsiades CS, Koutsilieris M. Molecular biology and cellular physio-
logy of refractoriness to androgen ablation therapy in advanced
prostate cancer should be included in prospective trials armed
prostate cancer. Exp Opin Invest Drugs 2001; 10: 1099–1115.
to demonstrate either palliative or survival impact. Although
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 7, 2015
10. Quilty PM, Kirk D, Bolger JJ et al. A comparison of the palliative
these patients must be evaluated carefully before any deci-
effects of strontium-89 and external beam radiotherapy in metastatic
sions about treatment are made. Decisions are always prostate cancer. Radiother Oncol 1994; 31: 33–40.
multidisciplinary. Evaluation of treatment results must be 11. Collins C, Eary JF, Donaldson G et al. Samarium-153-EDTMP in
performed at each step of therapy. bone metastases of hormone refractory prostate carcinoma: a phase I/
II trial. J Nucl Med 1993; 34: 1839–1844.
12 . Farrugia D, Ansell W, Singh M et al. Stilboestrol plus adrenal
Acknowledgements
suppression as salvage treatment for patients failing treatment with
The authors thank Mrs Marie-France Mévélec for help in luteinizing hormone-releasing hormone analogues and orchidect-
the preparation of the material and Mrs Marie-Dominique omy. Br J Urol Int 2000; 85: 1069–1073.
Reynaud for editing the manuscript. 13. Bayley A, Milosevic M, Blend R et al. A prospective study of factors
predicting clinically occult spinal cord compression in patients with
metastatic prostate carcinoma. Cancer 2001; 92: 303–310.
References 14. Oefelein MG, Ricchuiti V, Conrad W et al. Skeletal fracture associ-
1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of ated with androgen suppression induced osteoporosis: the clinical
castration, of estrogen and androgen injection on serum phosphatases incidence and risk factors for patients with prostate cancer. J Urol
in metastatic carcinoma of the prostate. Cancer J Clin 1972; 22: 2001; 166: 1724–1728.
232–240. 15. Ransom DT, Dinapoli RP, Richardson RL. Cranial nerve lesions due
2. Bubendorf L, Schopfer A, Wagner U et al. Metastatic patterns of to base of the skull metastases in prostate carcinoma. Cancer 1990;
prostate cancer: an autopsy study of 1589 patients. Hum Pathol 2000; 65: 586–589.
31: 578–583. 16. Burgess NA, Hudd C, Rees RW. Haemostatic pitfalls in advanced
3. Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial prostatic cancer. Br J Urol 1993; 71: 231–233.
of leuprolide with and without flutamide in prostatic carcinoma. 17. Balducci L, Extermann M. Management of cancer in the older
N Engl J Med 1989; 321: 419–424. person: a practical approach. Oncologist 2000; 5: 224–237.You can also read
