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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 metastatic bone pain: single fraction versus multifraction radiotherapy-A systematic review of randomised trials. Clin Oncol 2003; 15:345-352. 20. Coia LR, Aaronson N, Linggood R, et al. A report of the consensus workshop panel on the treatment of brain metastases. Int J Radiat Oncol Biol Phys 1992; 23(1):223-227. 21. Priestman TJ, Dunn J, Brada M, et al. Final rsults of the Royal College of Radiologists’ trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol 1996; 8:308-315. 22. Haie-Meder C, Pellae-Cosset B, Laplanche A, et al. Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol 1993; 26: 111-116. 23. Osoba D, MacDonald N, Principles governing the use of cancer chemotherapy in palliative care. In Doyle D, Hanks GEC, MacDonald N ed. Oxford Textbook of Palliative Medicine 2nd edition. Oxford, University Press 1998, 249-267. 24. Archer VR, Billingham LJ, Cullen MH: Palliative Chemotherapy: No Longer a Contradiction in Terms. The Oncologists 1999; 4:4:470-477. 25. Kim A, Fall P, Wang D: Palliative Care: Optimizing Quality of Life. JAOA 2005; 105(S5):S9-S14- 26. Tannock IF, Osoba D et al: Chemotherapy with mitoxantrone prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer. A Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14(6): 1756-1764. 27. Glimelius B, Hoffman R et al. Cost-effectiveness of palliative chemotherapy in advanced gastrointestinal cancer. Ann Oncol 1995; 6(3):267-274. 28. Tannock IF, Boyd NF, Deboer G et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988;6:1377-1387. 29. Ihde DC. Chemotherapy of lung cancer. N Engl J Med 1992;327: 1434-1441. 30. Fernandez CF, Rosell R, Abad-Esteve A et al. Quality of life during chemotherapy in non-small cell lung cancer patients. Acta Oncol 1989;28:29-33. 31. Ozols RF. Treatment goals in ovarian cancer. Int J Gynecol Cancer. 2005; 15(Sl 1):3-11. 32. Spiro SG. Management of lung cancer. BMJ 1990;301:1287-1288. 33. Rappe E, Pater JL, Willan A et al. Chemotherapy can prolong in survival in patients with advanced non-small cell lung cancer – report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633-641. 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