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4th Hong Kong Palliative Care Symposium________________HKSPM Newsletter 2007 Apr & Aug Issue 1 & 2 p 14
19. Sze WM, Shelly MD, Held I, et al. Palliation of
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Hormonal therapy and targeted therapy in palliative cancer care
Dr LO Sing-hung
Dept of Clinical Oncology, Tuen Mun Hospital
Correspondence: [email protected]
In patients with advanced cancer, chemotherapy,
hormonal therapy and targeted therapy are common
treatment modalities for systemic palliative treatment.
Majority of the chemotherapeutic agents affect cells in
proliferative phase (G1 to M phase of cell cycle) and
differentiate cancer cells from normal cells by their
higher rate of cell proliferation. Therefore normal cells
with high proliferation rate are frequently affected by
chemotherapy, causing adverse effects such as
marrow suppression or alopecia. On the other hand,
hormonal therapy and targeted therapy agents usually
retain the cancer cells in quiescence state (G0 to G1
phase) and the tumour growth is halted. These two
types of agents affect tumour cell through inhibition of
specific receptor or the growth factor that stimulate the
tumour cells. Hence they are more selective and their
adverse effects are more tolerable to fragile patients.
Hormonal Therapy
Breast Cancer
Sex hormonal related cancer, such as breast
cancer and prostate cancer, frequently response to
hormonal treatment. Estrogen receptor (ER) is
commonly present in breast cancer, especially in the
elderly. In patients with ER positive advanced breast
cancer, hormonal manipulation is an effective
treatment. Hormonal manipulation is achieved by
either blockade of the ER in cancer cell or removal of
hormone production source. Blockade of the ER by
tamoxifen is the most common form of hormonal
therapy in patients with advanced breast cancer. The
overall response rate and duration of response of
tamoxifen in patients with ER positive advanced
breast cancer is 70-80% and 12-16 months
4th Hong Kong Palliative Care Symposium________________HKSPM Newsletter 2007 Apr & Aug Issue 1 & 2 p 16
respectively, compared to 50-70% and 8-12 months in
palliative chemotherapy. The onset time of tamoxifen
is 2-3 months. Common side effect of tamoxifen
includes
post-menopausal
symptoms
and
thromboembolic events. Occasionally patients on
tamoxifen also have increased risk of uterine
malignancy
and
visual
disturbance.
In
peri-menopausal patients, removal of hormonal
production such as ovarian ablation by radiotherapy is
also useful. In post-menopausal patients, the adrenal
glands are important source of estrogen. Using
aromatase inhibitors (AI) such as anastrozole, letrozle
or exemestane can reduce the production of estrogen
and effectively control breast cancer. The efficacy of AI
is comparable to tamoxifen in randomized controlled
clinical trials1,2 . AI can be used as first line treatment or
in patients failed tamoxifen. Megestrol remains a
second or third line treatment option in patients who
failed other hormonal treatment.
Prostate Cancer
Prostate cancer is commonly androgen
dependent. Hence hormonal treatment is also
effective in patients with advanced prostate cancer.
The treatment principle is similar to breast cancer. The
production of androgen can be cut off by 1) surgical
castration through orchidectomy; 2) medical
castration by luteinizing hormone releasing hormone
(LHRH) injection to abolish the surge of LHRH in the
hypothalamus-pituitary axis hence reduce the
stimulation to testes. Both treatment options have
similar efficacy. Orchidectomy has an advantage of a
relatively simple operation, free from compliance
problem and quick response in symptom improvement
e.g. reduction of metastatic bone pain in terms of a
few days. LHRH monthly subcutaneous depot
injections such as leuprorelin or goserelin are equally
effective, with 80% response rate. It has an advantage
of reversibility. However in the first injection of LHRH,
there is an initial stimulation of testes hence increase
production of androgen. The tumour may be activated
(flare-up phenomenon) with an increase of symptoms
(including cord compression in case of spine
metastasis). Therefore patients with initial LHRH
treatment have to be covered by anti-androgen for 3
days before and 3 weeks after the LHRH injection.
Anti-androgen is another alternative of hormonal
treatment in prostate cancer. Drugs like flutamide,
bicalutamide or cyproterone are androgen receptor
blocker. Anti-androgen can be used as monotherapy,
in combination with orchidectomy or medical
castration, or as salvage treatment in patients initially
response to surgical or medical castration.
Adverse effects of hormonal manipulation in
prostate cancer patients include loss of libido,
impotence, fatigue and loss of muscle bulk. The best
modality of hormonal treatment in prostate cancer is
difficult to define. Longer disease control time may be
associated with more adverse effects on deterioration
in physical capacity and sexual interest 3,4. The
possibility of intermittent versus continuous hormonal
treatment still need further exploration.
Targeted Therapy
Targeted therapy is a relatively new treatment
modality. The medication used in targeted therapy
blocks the growth of cancer cells by interfering with
the specific targeted molecules needed for
carcinogenesis or tumour growth. The agents used in
targeted therapy are either small molecule or
monoclonal antibody. The commonly used targeted
therapy agents are listed in table 1.
Gefitinib is a typical example of targeted therapy
agent. It is an oral medication which blocks the
tyrosine kinase component in the epidermal growth
factor receptor (EGFR). Stimulation of the EGFR is a
key step in certain types of cancer cell such as
non-small cell lung cancer (NSCLC). In early clinical
trials, the efficacy of gefitinib in patients with NSCLC
refractory to chemotherapy can be drastic 5. Majority
of the responders show improvement of symptoms
within 14 days after administration 6,7. In phase III
clinical trials gefitinib as second line treatment
demonstrates a statistically significant improvement of
time-to-treatment-failure over the placebo group (3
months vs 2.6 months, p=0.0005) but only shows
improvement of overall survival in non-smoker
(Hazard ratio 0.67, CI 95% 0.49-0.91, P=0.011) 8. An
advantage has also been shown in Asian ethnic origin.
Adverse effects of gefitinib include diarrhoea,
dermatological reaction such as skin rash and acne,
nausea and vomiting. Around 1.5% patients develop
interstitial lung disease, which is potentially fatal.
Erlotinib is another EGFR inhibitor in NSCLC. In
phase III clinical trial it shows an improvement in
overall survival (median overall survival 6.7 months vs
4.7 months, p=0.001) as a second line treatment 9. A
better response is seen in female, adenocarcinoma
subtype and non-smoker. Similar response predictor
has been previously identified in gefitinib as well. The
phase III studies in gefitinib and erlotinib strongly
suggest that proper patient selection is the key to
success. In fact in the subset analysis of the two
phase III studies, the overall survival in the treatment
group and placebo group is very similar for smoker.
Besides clinical history, the use of laboratory response
predictors such as specific oncogene mutation or
EGFR subtype mutation have been actively explored
which will ultimately leads to better patient selection
for treatment 5.
4th Hong Kong Palliative Care Symposium________________HKSPM Newsletter 2007 Apr & Aug Issue 1 & 2 p 17
Besides EGFR, vascular endothelial growth
factor (VEGF) is another important target. The growth
of tumour must be accompanied by the growth of
blood vessels in order to maintain oxygen and
nutrition supplies to cancer cells. The stimulation of
vascular growth by tumour cell has been noticed as
early as in the 1930s. Bevacizumab is a VEGF
inhibitor and its anti-tumour activity has been well
demonstrated in phase III clinical trials.
Certainly more targeted therapy agents are
coming through new researches and the prospect is
promising. However the cost of targeted therapy is
also high. The monthly cost for gefitinib and erlotinib is
$14000 and $18000 respectively in this locality.
Moreover these two drugs have to be administered
every day indefinitely until disease progression.
Fortunately, or unfortunately, a minority of patients’
disease may be controlled with the medication for
more than 1 year. The financial burden can be huge. A
solution to this financial and ethical problem is
urgently needed.
Conclusion
Hormonal therapy and targeted therapy are two
important treatment modalities in advanced cancer
patients. With proper patient selection by clinical
history and laboratory means, the two treatments can
effectively palliate patient’s symptom as well as
prolong survival. In general, their adverse effects are
tolerable even in patients with poor performance
status. High treatment cost in targeted therapy is a
major obstacle.
References
1. J. Bonneterre, B. Thurlimann, J.F.R. Robertson, et al. Anastrozole
versus tamoxifen as first-line therapy for advanced breast
cancer in 668 postmenopausal women: results of the tamoxifen
or arimidex randomized group efficacy and tolerability study.
Journal of Clinical Oncology 2000; 18:3748-3757.
2. H. Mouridsen, M Gershanovich, Y Sun, et al. Phase III study of
letrozole versus tamoxifen as first-line therapy of advanced
breast cancer in postmenopausal women: analysis of survival
and update of efficacy from the International Letrozole Breast
Cancer Group. Journal of Clinical Oncology 2003; 21:
2101-2109.
3. M.K. Brawer. Hormonal therapy for prostate cancer. Reveiws in
Urology 2006; 8 Suppl 2: S35-47.
4. J. Anderson. The role of antiandrogen monotherapy in the
treatment of prostate cancer. British Journal of Urology
International 2003; 91: 455-461.
5. T. Lynch, D. Bell, R. Sordella, et al. Activiting mutations in the
epidermal growth factor receptor underlying responsiveness of
non-small cell lung cancer to gefitinib. The New England Journal
of Medicine 2004; 350: 2129-2139.
6. M. Fukuoka, S. Yano, G. Giaccone, et al. Multi-institutional
randomized phase II trial of gefitinib for previously treated
patients with advanced non-small-cell lung cancer. Journal of
Clinical Oncology 2003; 21: 2237–2246.
7. M. Kris, R Natale, R Herbst, et al. Efficacy of gefitinib, an inhibitor
of the epidermal growth factor receptor tyrosine kinase, in
symptomatic patients with non-small cell lung cancer: a
randomized trial. The Journal of the American Medical
Association 2003; 290: 2149–2158.
8. N. Thatcher, A. Chang, P. Parikh, et al. Gefitinib plus best
supportive care in previously treated patients with refractory
advanced non-small-cell lung cancer: results from a
randomized, placebo-controlled, multicentre study (Iressa
Survival Evaluation in Lung Cancer). Lancet 2005; 366:1527-37.
9.
F. Shepherd, J. Pereira, T Ciuleanu, et al. Erlotinib in
previously treated non-small cell lung cancer. The New
England Journal of Medicine 2005; 353: 123-132.
Table 1
Types
Small Molecules
Monoclonal Antibodies
Name
Trade Name
Target/Mechanism
Imatinib (STI-571)
Gleevec
TK bcr-abl
Gefitinib (ZD1839)
Erlotinib
Bortezomib
Iressa
Tarceva
Velcade
TK Her1 (ErbB-1)
TK
Proteasome
Rituximab (antiCD20)
Trastuzumab (anti-HER2)
Cetuximab
Herceptin
Erbitux
Bevacizumab
Avastin
CD20, antibody-dependent
cellular cytotoxicity &
complement-mediated cytotoxicity
TK Her2(ErbB-2)
EGFR, antibody-dependent
cellular cytotoxicity
VEGF
Indication
CML
GIST
DFP
NSCLC
NSCLC
MM
NHL
Breast cancer
Colon cancer
H&N cancer
Colon cancer
Breast cancer
NSCLC
Abbreviations: TK - tyrosine kinase, CML - chronic myeloid leukaemia, GIST - gastrointestinal stromal tumour, DFP - dermatofibromatosis
protuberence, NSCLC - non-small cell lung cancer, MM - multiple myeloma, NHL - non-Hodgkin’s lymphoma, H&N – head and neck
cancer, VEGF – vascular endothelial growth factor