1. 門 診 處 方 討 論門 診 處 方 討 論 Thalidomide 用於癌症的治療 報告者 : 邱英滋藥師 95.04.24

2. Thalidomide 之 Clinical Applications FDA Approved Indications  Erythema Nodosum Leprosum (ENL) use dose ： 100-400mg/day Therapeutic use  Cancer (Hepatocellular carcinoma,Multiple myeloma, Prostate cancer, Breast cancer,Renal cell carcinoma......) use dose ： 100-1200mg/day

3. Thalidomide 於 cancer 治療之機轉 Exact mechanism by which thalidomide produces beneficial effects in cancer patients is unknown, several proposed mechanisms exist: 1) thalidomide may inhibit growth and survival of myeloma cells by oxidative damage to DNA mediated by free radicals. (Hideshima et al, 2000)

4. Thalidomide–DNA intercalation

5. Thalidomide 於 cancer 治療之機轉 2) may alter the secretion and biologic activity of cytokines (eg, interleukin-6, 1- beta, and 10, tumor necrosis factor). 3) may reduce angiogenesis by inhibiting vascular endothelial growth factor and basic fibroblast growth factor 2. (Raje & Anderson, 1999a) 4) antiinflammatory and immunemodulatory

6. 服藥期間： 1/11-3/10

7. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (1) 於 1999.3-2000.3 間罹患 Hepatocellular carcinoma(HCC) 的 37 位病患給予 thalidomide ，劑量由 400mg/day( 第一週 ) 慢慢增加至 1000mg/day( 第五週 ) ， BID 給 藥，持續 8 週。 Reference: Patt YZ. Hassan MM. Lozano RD. Nooka AK. Schnirer II. Zeldis JB. Abbruzzese JL. Brown TD. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer. 103(4):749-55, 2005 Feb 15.

8. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (1) With a 5% PR rate, a 5% MR rate, and a 31% SD rate (95% confidence interval [95%CI], 16- 51%), and 20 patients(61%; 95%CI, 42-78%) had disease progression.The overall median survival was 6.8 months. The results indicate that thalidomide mostly may offer HCC patients disease stabilization.

9. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (1) In fact, only 48% of patients tolerated a daily dose > 800 mg if it was delivered at bedtime. In view of the significant neurologic toxicity, thalidomide monotherapy at the high doses studied cannot be recommended for the treatment of HCC.

10. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (2) Sixty-eight patients with unresectable and nonembolizable HCC in a compassionate treatment program of oral thalidomide. Tumor response and treatment-related toxicity were prospectively followed. Thalidomide was given at a starting dose of 200 mg per day. The dose was gradually escalated in 100- mg steps up to 600 mg per day if no limiting toxicities developed. Reference: Chiun Hsua, Chiung-Nien Chen, Li-Tzong Chen, Chen-Yao Wu, Pei-Ming Yang, Ming- Yang Lai, Po-Huang Lee, Ann-Lii Cheng. Low-Dose Thalidomide Treatment for Advanced Hepatocellular Carcinoma. Oncology 2003;65:242-249

11. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (2) Sixty-three patients were evaluable for response. The duration of response was 50+, 24.6, 11.6+ and 8.7+ weeks, respectively. All 4 responders had a dramatic decrease in α -fetoprotein ( α -FP) levels. The median overall survival for all of the 68 patients was 18.7 weeks (95% CI 11.8- 25.6) with a 1-year survival rate of 27.6%.

12. Thalidomide 於 Hepatocellular carcinoma 治療之臨床證據 (2) All responders responded at a dose equal to or less than 300 mg per day. Toxicities of thalidomide were generally manageable, and only 16, 6, and 0 patients developed grade 2, 3, and 4 toxicities, respectively. Conclusion: Low-dose thalidomide is safe and induces unequivocal tumor response in a minority of patients with advanced HCC.

15. Thalidomide 之 Adverse Reactions Teratogenicity Neurologic neuropathy somnolence Edema 、 constipation 、 fatigue 、 nausea

16. Thalidomide 於 cancer 之結論 FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B Referevence: Micromedex

17. References  MICROMEDEX  Patt YZ. Hassan MM. Lozano RD. Nooka AK. Schnirer II. Zeldis JB. Abbruzzese JL. Brown TD. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer. 103(4):749-55, 2005 Feb 15.  Chiun Hsua, Chiung-Nien Chen, Li-Tzong Chen, Chen-Yao Wu, Pei-Ming Yang, Ming-Yang Lai, Po-Huang Lee, Ann-Lii Cheng. Low-Dose Thalidomide Treatment for Advanced Hepatocellular Carcinoma. Oncology 2003;65:242-249