Komplikacje leczenia hormonalnego (art. w j. ang.)

Komplikacje leczenia hormonalnego (art. w j. ang.)

Nieprzeczytany postautor: zosia bluszcz » 20 lip 2016, 15:40

Artykul na temat komplikacji zwiazanych ze stosowaniem leczenia hormonalnego w raku prostaty.
(Ilustracje w linku)


Androgen deprivation therapy for prostate cancer and its complications

ALVAN J. POPE AND PAUL D. ABEL

This article focuses on the hormonal treatment of prostate cancer by the reduction of androgen activity. The authors outline the under-recognised complications that can be caused by the castration effect of androgen deprivation therapy.

Mr A.J. Pope, MD, FRCS(Urol), Consultant Urologist, Hillingdon Hospital NHS Trust; Mr P.D. Abel, ChM, FRCS, Professor and Honorary Consultant Urologist, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London. Series Editor: Professor David Dearnaley, MA, MD, FRCP, FRCR, Consultant Oncologist, Royal Marsden Hospital, Sutton, Surrey.


Androgen deprivation therapy (ADT) is used for men with advanced (incurable) prostate cancer and often suppresses their disease for many years (median response with bone metastases is about two years). It is also used as an adjunct to radiotherapy, but is not by itself a curative treatment for prostate cancer. In very elderly or unfit men who would be managed initially by observation, ADT would be started only when there was definite evidence of disease progression, such as the development of bone metastases (Figure 1).
It has been known for more than half a century that prostate cancer is hormone dependent, requiring androgens to develop and grow.
Androgen deprivation therapy slows the progression of prostate cancer and early studies suggested that treating prostate cancer patients with hormonal therapy (either orchidectomy or oral oestrogen in those days) showed an advantage in both quality of life and survival compared with untreated patients.1

There are an estimated two million prostate cancer survivors in North America, of whom up to 700000 are either chemically or surgically castrated (possibly one million worldwide). Given the detection rate for prostate cancer, some 4 per cent of all men in Caucasian populations can expect to be chemically or surgically castrated before they die.2

Hormone therapy in the context of prostate cancer is generally taken to mean a treatment that reduces serum testosterone to castrate levels and/or blocks androgen receptor binding, thereby depriving prostate cells of their primary mitogenic source and delaying progression.

These therapies include surgery, eg orchidectomy, or pharmacological treatment, eg luteinising hormone-releasing hormone (LHRH) agonists/antagonists, oestrogens and non-steroidal antiandrogens (flutamide, bicalutamide).

In the UK, most GPs will be familiar with the use of the LHRH agonists goserelin (Zoladex) or leuprorelin (Prostap) given subcutaneously and triptorelin (Decapeptyl) given intramuscularly as long- acting depot preparations.


Timing of ADT
As many men with advanced prostate cancer have com- peting causes of mortality, most early studies failed to show an advantage in overall survival, resulting in con- troversy as to optimum timing of hormonal therapy. The use of oral oestrogens was shown to decrease overall survival from cardiovascular and thromboembolic toxicity, despite improved disease-specific survival, although the dose given to maintain castrate testoster- one levels would now be considered excessive.3
As a result, although ADT slowed disease progression, the lack of any prolongation in overall survival led to postponing treatment until symptomatic progression occurred, usually from painful bone metastases. This policy meant that many men might never receive ADT before dying.

A recent randomised trial of immediate versus delayed ADT revealed that about 40 per cent of men died from competing causes before needing ADT.4
Further analysis revealed that presenting prostate- specific antigen (PSA) values could guide decision- making toward selection of men most likely to benefit from ADT.5

By contrast, an earlier Medical Research Council (MRC) study is often cited to support early androgen suppression as more effective than delayed therapy in not only prolonging disease-specific survival, but also reducing the risk of serious disease-related complications such as pathological fractures, spinal cord com- pression, ureteric obstruction or urinary retention.6
However, those men destined to die from their comorbidity rather than prostate cancer may never derive benefit from ADT, but still suffer the side-effects.

The potential to preserve sexual potency and libido with non-steroidal antiandrogen monotherapy makes this a more attractive form of ADT than LHRH agonists for younger and sexually active men, although it may be less effective than LHRH, especially in more advanced disease.

The Early Prostate Cancer Program was an industry-sponsored multinational, randomised, double- blind, placebo-controlled study comprising over 8000 men,
the largest clinical trial ever performed in prostate cancer. It compared early treatment with bicalutamide 150mg either alone or as adjuvant to treatment with curative intent in non-metastatic prostate cancer.
There was an advantage with delayed disease progression for all groups except men who had a radical prostatectomy, but no benefit to overall survival,
although there was a trend favouring treatment of locally advanced disease.7


LHRH agonists and tumour flare
Tumour flare can occur when starting treatment with LHRH agonists, because an initial surge of LH is released with a corresponding increase in serum testos- terone before it is suppressed. This phenomenon carries a particular risk of clinical consequences in patients with bone metastases or urinary obstruction, so should be prevented by pretreating with antiandrogens for up to two weeks before the first LHRH implant. The antiandrogen can be safely stopped a couple of weeks later.
This flare effect does not occur with the new generation of LHRH antagonists, such as degarelix (Firmagon),8 which also produce a more rapid fall in testosterone to castrate levels than LHRH agonists. This rapid fall in testosterone is likely to be of clinical benefit to only a small subgroup of patients, such as those at imminent risk of serious morbidity, including spinal cord compression, pathological fracture or renal failure.


ADT as adjuvant therapy to radical local treatment
ADT is recommended as neoadjuvant and adjuvant therapy in some men with localised prostate cancer undergoing radical radiotherapy with curative intent. Typical regimens start with ADT three months before radiotherapy, continuing for either six months or two to three years for men at intermediate and high risk for disease progression, respectively.
With three years of ADT plus radiotherapy, a significant five-year overall survival advantage (78 per cent versus 62 per cent) has been shown in high-risk disease.9
There is also a significant survival advantage for six months’ treatment with ADT for men with intermediate-risk disease without significant comorbidity,10
but no similar advantage with low- risk disease has yet been demonstrated, although studies are ongoing.
No such benefit has been reported either for adjuvant ADT in men undergoing radical prostatectomy, although if positive pelvic lymph nodes are found after surgery, immediate ADT is recommended.11


Intermittent ADT
For clinicians keen to minimise morbidity, cyclical ADT treatment is an option. ADT is administered for a sufficient time to suppress PSA maximally (usually six to nine months), and then stopped to allow PSA to rise to a predetermined level, before restarting.
The optimum timing for the treatment phase and the appropriate PSA level that merits restarting ADT is unclear and varies between patients with differing extents of disease.
In general, men spend more time off ADT than on it, potentially offering advantages in reducing treatment- related morbidity and cost.
Initial hopes that treating in this way could delay onset of castration resistance and increase survival compared with continuous ADT remain unproven, so this is largely investigational.12


Choice of LHRH
The various LHRH agonists have no significant differences in outcome or adverse effects and are inter- changeable.
Goserelin is a solid implant preparation delivered through a relatively wide-bore needle, whereas leuprorelin and triptorelin are liquid formulations.
These are all available in either one- or three-month formulations.
Histrelin (Vantas) is a new 12-month implant formulation, which requires a small surgical incision to insert.
There can be large differences between the costs of these drugs and, as a result, local prescribing guidelines may vary.


ADT resistance and further therapy
If men with prostate cancer treated by LHRH live long enough, treatment resistance develops, identified initially by rising PSA, often without evidence of meta- stases. These men usually appear well, but present a challenge both in timing and choice of subsequent treatment.

Traditionally, a stepwise approach is used.
=> Initially, second-line hormonal therapy with an antiandrogen (flutamide or bicalutamide) is added (except if already on both as maximal androgen ablation, when the antiandrogen would be stopped and about one-third of men demonstrate PSA reduction, maintained for a few months).
=> Following failure of second-line therapy, third- line agents, most commonly low-dose oestrogen or steroids, are used; a minority respond, although some- times impressively.
Men who responded well to initial hormonal manipulation are more likely to have good outcomes.

Non-hormonal treatments directed at sites of progression, usually bone related, can also be used.

Onset of major complications, either skeletally related events or urinary obstruction, dictate specific treatments, but also indicate onset of the terminal phase of disease and need for specialist palliative care.

Cytotoxic chemotherapy has usually been considered only after all variations of ADT have been exhausted, but with the more effective and better tolerated docetaxel (Taxotere), is more frequently offered earlier in the clinical course (several scenarios are currently being tested in clinical trials).

(Artykul jest z 2010 r. - wyniki badania STAMPEDE opublikowano dopiero w 2015. zb)



Complications of ADT
It is generally poorly appreciated that castrate testosterone levels resulting from ADT produce an acute andropause (castration syndrome), like the female menopause, with all the attendant adverse effects.
Recognising this is increasingly important as the indications for ADT widen and duration of therapy extends through longer periods of time, sometimes over 10 years.
ADT reduces testosterone and oestrogen levels by about 95 per cent and 80 per cent, respectively (because oestrogen is produced through aromatisation of testosterone).
Testosterone deficiency is associated with muscle weakness, diabetes, changes in body composition and erectile dysfunction, whereas adverse effects of oestrogen deficiency include increased fracture risk, lipid changes, memory loss, gynaecomastia and hot flushes.13,14


=> Osteoporosis
Recently, large studies have established a strong relationship between ADT, decreased bone mineral density (BMD) and fractures.
Of 50 613 men with prostate can- cer, 31 per cent had ADT. Up to 60 months post- treatment initiation, 19.4 per cent on ADT compared to 12.6 per cent not on ADT had a fracture (p<0.001). The longer the duration of ADT, the greater the fracture risk.15

In more than 11600 men with non-metastatic prostate cancer, about one-third on LHRH agonists, there was a significantly higher risk of any fracture with ADT (21 per cent) compared to controls.16
Lee et al. reported a mean BMD loss at the hip of 1.9 per cent in 65 men on LHRH agonists over 12 months.17
Higano’s review reported up to 4.6 per cent BMD loss during the first year of ADT.18


=> Cardiovascular effects, insulin sensitivity and lipid profiles
Newly diagnosed prostate cancer patients who receive ADT for at least one year were found to have a 20 per cent higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT, apparent within 12 months of beginning treatment.19
Nanda et al. compared the effect of neoadjuvant ADT in two groups of men with a median follow-up over five years;
one group had pre-existing coronary-artery-disease- induced congestive heart failure or myocardial infarction and the other group had no cardiovascular morbidity.
Those with pre-existing coronary artery disease experienced significant increased risk of all-cause mortality (26 per cent versus 11 per cent).
By contrast, ADT was not associated with altered all-cause mortality in those without comorbidity.10,20

Nevertheless, it is important to emphasise that there has been an improvement in both overall survival and prostate-cancer-specific mortality,
demonstrated in randomised controlled trials of short and long courses of adjuvant hormonal therapy with radiotherapy.9,10

In almost 5000 men over 65 years undergoing radical prostatectomy, the five-year cumulative incidence of cardiovascular death was 5.5 per cent in patients receiving ADT versus 2 per cent in those who were not.21

ADT decreases insulin sensitivity and lean mass while increasing fat mass accompanied by rising low- and high-density lipoprotein (HDL) cholesterol and tri- glycerides.
This is similar to the metabolic syndrome, but by contrast there is an increase in subcutaneous fat and HDL cholesterol with ADT.22
A study of more than 73000 men with prostate cancer showed that those on ADT had an excess risk of diabetes (hazard ratio
1.44), coronary heart disease (HR 1.16), myocardial infarction (HR 1.11) and sudden death (HR 1.16); those undergoing bilateral orchidectomy had a significant increase in diabetes (HR 1.34).23



=> Anaemia
Normochromic normocytic anaemia is associated with ADT and temporally related to its initiation, usually resolving after discontinuation.
Anaemia and associated symptoms in these patients was corrected with subcutaneous recombinant human erythropoietin.24
Curtis et al. also showed that ADT resulted in significantly reduced haemoglobin levels into the anaemic range, with some patients becoming symptomatic.25


=> Cognitive dysfunction
Cognitive dysfunction associated with ADT may be due to oestrogen or testosterone deficiency (or both); receptors for both hormones are found in the relevant areas of the brain.
Beer et al. compared two groups of men on ADT who were, or were not, given additional oestrogen, together with a third control group of age-matched healthy men.
Men receiving ADT were significantly poorer in cognitive scores at baseline than healthy patients.
When retested, those receiving oestrogen showed a significant improvement, whereas those not receiving oestrogen had no improvement. There was no change in healthy men.26

A systematic review of the impact of ADT on cognition in patients with prostate cancer reported that studies were designed relatively well but suffered from small sample sizes, concluding that strong evidence linked ADT to subtle but significant cognitive declines. Between 47 per cent and 69 per cent of men on ADT declined in at least one cognitive area, most often visuospatial or executive functioning.27


=> Frailty
Frailty describes older individuals with limited physiological reserve at significant risk for adverse outcomes.
ADT may accelerate development of frailty in vulnerable older men with prostate cancer. Given the association of frailty with hospitalisation and death, these consequences need careful consideration when initiating therapy in older patients. Older men receiving long- term ADT exhibited significant functional and physical impairment and were at greater risk of falls than similar age cohorts.28,29


=> Hot flushes
Hot flushes are the most common early side-effects seen with LHRH.
A recent controlled trial concluded that medroxyprogesterone was the most effective and least toxic therapy, but cyproterone acetate is also effective 30
at a small dose of 50–100mg daily.


=> Breast pain and gynaecomastia
Gynaecomastia is a major problem and often distressing to men treated with both non-steroidal antiandrogens (especially during monotherapy with bicalutamide 150mg/day) and oestrogen, but also, to a lesser extent, with LHRH (Figure 2).
The exact cause is unclear, but may be related to changes in the ratio of testosterone to oestrogen.13
Symptoms may be improved with tamoxifen in a dose-dependent fashion, with daily doses of 10–20mg having more effect than, for example, tamoxifen 20mg given weekly.31
Alternatively a single fraction (12Gy) of breast-bud radiotherapy can be used for stilboestrol-induced gynaecomastia, as tamoxifen might
reduce the efficacy of oestrogens – but should ideally be administered before ADT begins, for most benefit.
Radiotherapy is less effective than tamoxifen for antiandrogen-induced gynaecomastia.32


Managing the man on ADT for toxicity
In view of the inherent adverse events associated with ADT, it would seem prudent to consider baseline (and follow-up) assessment of some fundamental areas of risk, including investigations such as DEXA scanning for bone density and serum levels of lipids and cholesterol prior to and possibly during treatment, although the evidence for this remains undetermined.


Parenteral oestrogen – an alternative to LHRH?
Oral oestrogen has long been abandoned as first-line therapy for prostate cancer because of the marked cardiovascular toxicity due to first pass through the liver. However, parenteral oestrogen appears to reduce this risk substantially and mitigate the effects of castration syndrome.

In the final evaluation of the largest study of parenteral oestrogen to date,33 855 of the 910 patients (all with skeletal metastases) had died.
LHRH or bilateral orchidectomy (both combined with the antiandrogen flutamide) was compared with intramuscular polyestradiol phosphate (PEP).
Regarding cardiovascular mortality, there was no significant difference between the groups (39 versus 38 men).
Regarding cardiovascular morbidity, there was a significant increase in the PEP group (71 versus 50 men).
This was offset by serious skeletal morbidity in the LHRH/orchidectomy group (0 versus 18 men).
There was no significant difference in overall, disease-specific or progression-free biochemical survival.

The authors concluded that PEP had an anticancer efficacy equal to LHRH/orchidectomy.
Although PEP did not increase cardiovascular mortality, there was a higher risk of non-fatal cardiovascular events, which should be balanced against skeletal complications in the LHRH/orchidectomy group.

The MRC Clinical Trials Unit is comparing transdermal oestrogen patches with LHRH in men with prostate cancer (Prostate Adenocarcinoma TransCutaneous Hormones – PATCH study) (Figure 3). Patches are painless to apply and, if toxicity develops, can be removed immediately, in contrast to intramuscular PEP.34,35


Summary
ADT offers useful palliation in incurable prostate cancer as well as a survival advantage when used as neoadjuvant/adjuvant therapy with radiotherapy.
The best timing and duration of therapy remain under investigation. Castration brings with it many serious adverse events that have only recently gained the attention of clinicians.

Conflict of interest
PDA is Principal investigator for the PATCH study and has received grant funding from CR-UK. He is a consultant for Ascend pharmaceuticals.

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