爱必妥用于化疗失败后的 复发和/转移性头颈部鳞癌 (R&M SCCHN）

Presentation on theme: "爱必妥用于化疗失败后的 复发和/转移性头颈部鳞癌 (R&M SCCHN）"— Presentation transcript:

1 爱必妥用于化疗失败后的 复发和/转移性头颈部鳞癌 (R&M SCCHN）
- Patients with recurrent and/or metastatic SCCHN failing on chemotherapy have very limited therapeutic options. There is currently no standard therapeutic approach for these patients who have a very poor prognosis. - In a retrospective study of 151 such patients treated with various approaches, including further CT and CRT, the response rate was under 3% and the median survival was 3 months.[1] - There is an unmet need for better alternative treatments. 1. Leon X, Hitt R, Constenla M, et al. Clin Oncol (R Coll Radiol) 2005;17:

2 R&M SCCHN: 简介 50% 以上的新诊断病例不能治愈且最终局部复发或远处转移。10% 的新诊断病例伴有远处转移
治疗选择: 化疗 (CT) - 二次放疗 挽救性手术 最佳支持治疗 (BSC) 以顺铂为基础的化疗: 有效率: 30% 总生存期: 6 months 铂类失败者： - 有效率：< 5％ - 总生存期：3个月

3 铂类治疗失败后的R&M SCCHN-简介 一项回顾性研究显示1 ： 151 例铂类治疗后疾病进展的患者 接受BSC 者为: 45%
接受化疗和/或放疗者: 55% ORR: 2.6% Disease Control rate: 15.2% 总生存: 3.4 months 1León X, et al. Clin Oncol 2005;17:418–424

4 EGFR 和TGF 的高水平表达将会降低无病生存和总生存
TGFa水平 低度 中度 高度 p=0.0001 1.0 0.8 0.6 0.4 0.2 无病生存比例 术后年数 EGFR 和TGF 的高水平表达将会降低无病生存和总生存 Grandis, et al. J Natl Cancer 1998;90:824–832

5 EGFR 表达与预后不良相关 头颈部癌的 EGFR 表达率为 90-100% EGFR 与以下情况相关: 无病生存降低 总生存降低
转移/侵袭风险增加 - The EGFR is expressed at high levels in SCCHN compared with normal mucosa,[1] and such levels are an early marker of SCCHN carcinogenesis.[2] In addition, EGFR is expressed in % of SCCHN.[3-5] - Tumor EGFR expression is usually associated with poor clinical prognosis in SCCHN in terms of decreased disease-free,[4,6-8] and overall survival.[6-9] High levels of EGFR expression in SCCHN are also associated with increased locoregional relapse following treatment.[6] - EGFR expression is associated with resistance of tumor cells to radiation[10,11] and chemotherapy.[12] Furthermore, pre-clinical models have indicated a correlation between the level of EGFR expression and the resistance of tumors to radiation.[13,14] 1. Grandis JR, Melhem MF, Barnes EL, Tweardy DJ. Cancer 1996;78: 2. Grandis JR, Tweardy DJ. Cancer Res 1993;53: 3. Christensen ME, Therkildsen MH, Hansen BL, et al. Eur Arch Otorhinolaryngol 1992;249: 4. Grandis JR, Melhem MF, Gooding WE, et al. J Natl Cancer Inst 1998;90: 5. Salomon DS, Brandt R, Ciardiello F, Normanno N. Crit Rev Oncol Hematol 1995;19: 6. Ang KK, Berkey BA, Tu X, et al. Cancer Res 2002;62: 7. Maurizi M, Almadori G, Ferrandina G, et al. Br J Cancer 1996;74: 8. Magne N, Pivot X, Bensadoun RJ, et al. Eur J Cancer 2001;37: 9. Hitt R, Ciruelos E, Amador ML, et al. Eur J Cancer 2005;41: 10. Liang K, Ang KK, Milas L, et al. Int J Radiat Oncol Biol Phys 2003;57: 11. Chakravarti A, Dicker A, Mehta M. Int J Radiat Oncol Biol Phys 2004;58: 12. Newby JC, Johnston SR, Smith IE, Dowsett M. Clin Cancer Res 1997;3: 13. Akimoto T, Hunter NR, Buchmiller L, et al. Clin Cancer Res 1999; 5: 14. Milas L, Fan Z, Andratschke NH, Ang KK. Int J Radiat Oncol Biol Phys 2004;58:

6 爱必妥用于 R&M SCCHN 的二线治疗 - Recurrent and/or metastatic SCCHN is usually treated with chemotherapy if surgery is not possible.[1] - Many compounds exhibit single-agent activity (eg cisplatin, carboplatin, methotrexate, 5-FU, bleomycin and taxanes), although combination regimens are commonly used.[2] - Cisplatin has been regarded as the most important therapeutic agent and is the basis of many combination regimens for patients with recurrent and/or metastatic SCCHN.[2] - The synergy demonstrated by ERBITUX in combination with cisplatin in pre-clinical studies may prove of value when treating patients with recurrent and/or metastatic SCCHN in the first-line setting. 1. Cohen EE, Lingen MW, Vokes EE. J Clin Oncol 2004;22: 2. Schantz SP, Harrison LB, Forastiere A. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita VT, Hellman SA, Rosenberg SA, eds. Cancer. Principles and practice of oncology. Philadelphia: Lippincott Williams and Wilkins, 2001:

7 西妥昔单抗 (爱必妥) 用于 一线治疗失败的 R&M SCCHN的 荟萃分析
Vermorken J, Bourhis J, Trigo J, Kies M, Leon X, Mueser M, Amellal N, Schueler A, Baselga J - A phase II study has shown the activity of ERBITUX monotherapy in the treatment of recurrent and/or metastatic SCCHN that has progressed on prior platinum-based therapy.[1] - To place these results into context with what might normally be expected in such a patient population, the results from the ERBITUX monotherapy study were compared with those from a retrospective study of patients receiving a variety of second-line treatments after progression on platinum-based therapy.[2] 1. Trigo J, Hitt P, Koralewski E, et al. J Clin Oncol 2004;22(14S):Abstract 5502 Virtual presentation: 2. Leon X, Hitt R, Constenla M, et al. Proc Am Soc Clin Oncol 2003;22:502:Abstract 2022. 3. Vermorken JB, Bourhis J, Trigo J, et al. J Clin Oncol 2005;23(16S):Abstract 5505 Virtual presentation: Vermorken et al. J Clin Oncol 2005;23(16S):Abstract 5505 Virtual presentation:

8 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 -研究设计
以铂类药物为基础治疗的患者出现疾病进展 复发和/或转移性SCCHN Trigo1 Baselga2 Herbst3 León4 爱必妥 初始每周400 mg/m2 随后 250 mg/m2 爱必妥 初始每周400 mg/m2 随后250 mg/m2 + 顺铂/卡铂 爱必妥 初始每周400 mg/m2 ， 之后250 mg/m2 ×4 疗程 +顺铂 75 或100 mg/m2， q3wk BSC 或单药治疗/ 联合治疗 CT或RT 50%的患者 于疾病进展后接受 爱必妥+ 顺铂/卡铂 治疗 疾病稳定 或治疗有效 爱必妥单药治疗 直至疾病进展 1Trigo, et al. J Clin Oncol 2004;22(Suppl. 14s):488s [Abstract No. 5502]; 2Baselga, et al. J Clin Oncol 2005;23:5568–5577; 3Herbst, et al. J Clin Oncol 2005;23:5578–5587; 4Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:418–424

9 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 -患者和疾病特征
Trigo1 (n=103) Baselga2 (n=96) Herbst3 (n=79) León4 (n=151) 特征 57 56 55 58 年龄: 中位数/平均 (岁) 80% 80% 80% 70%a 中位KPS评分 48% 41% 43% 34% 已经转移的患者％ 94% 98% 100%b – 表达EGFR的患者％ 15 15 N/A N/A 自疾病进展后的中位持续时间(天) 100% 100% 100% 100% 先前接受过铂类药物治疗％ A结果来自124例患者 b15 例患者没有得到合适的组织样本来测定EGFR N/A=未得到相关数据 KPS=体力状况评分 1Trigo, et al. J Clin Oncol 2004;22(Suppl. 14s):488s [Abstract No. 5502]; 2Baselga, et al. J Clin Oncol 2005;23:5568–5577; 3Herbst, et al. J Clin Oncol 2005;23:5578–5587; 4Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:418–424

10 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 - 纳入研究总结
作者 终点 主要终点 次要终点 患者例数 治疗方案 Trigo1 103 爱必妥 单药治疗 有效率(IRC) OS, TTP, TTR, PK Baselga2 96 爱必妥 + 顺铂或卡铂 有效率(IRC) OS, TTP, TTR, QoL Herbst3 79 爱必妥 + 顺铂 有效率 OS, TTP, TTR León4 151 铂类药物治疗失败后 各种TRT 治疗 有效率 OS, TTP IRC: 独立监察委员会 1Trigo, et al. J Clin Oncol 2004;22(Suppl. 14s):488s [Abstract No. 5502]; 2Baselga, et al. J Clin Oncol 2005;23:5568–5577; 3Herbst, et al. J Clin Oncol 2005;23:5578–5587; 4Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:418–424

11 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 - 铂类治疗失败的标准
Study Trigo1 Baselga2 Herbst3 León4 最后一次铂类治疗至疾病进展的时间 ≤30 days <30 days After 2 cyclesa 接受铂类治疗的最少周期数 2–6 cycles 2–4 cycles 2 cycles 最小给药剂量 顺铂 卡铂 60 mg/m2 300 mg/m2 or AUC 4 >60 mg/m2 250 mg/m2 75 mg/m2 — Can I ask whether it is possible to have the data as requested in my previous slide modification? Minimum cddp duration is clinically not so interesting most important would be median number of previous cddp cycles indicating also the range. The same holds for previous cddp dose. aProtocol amended to enroll patients who developed PD within 90 days 1Trigo, et al (2004); 2Baselga, et al (2005); 3Herbst, et al (2005); 4Leόn, et al (2005)

12 在铂类治疗失败的R&M SCCHN的二线治疗中 爱必妥为基础的治疗较传统治疗更为有效
Treatment N Overall response CR+PR (%) Disease control CR+PR+SD (%) Median OS months Median TTP months 爱必妥单药 103 13 46 5.9 2.3 爱必妥 + 顺铂/卡铂 96 10 53 6.1 2.8 爱必妥 + 顺铂 79 56 5.2 2.2 历史对照: 所有患者 151 3 15 3.4 N/A 仅接受化疗的患者 43 9 3.6 - ERBITUX monotherapy led to improved efficacy compared with various other second-line therapies. - ERBITUX monotherapy was associated with a response rate of 13% compared with 3% for all patients in the retrospective study. This effect was even more pronounced when the results with ERBITUX monotherapy were compared with those for a sub-group of patients in the retrospective study who received various second-line chemotherapy regimens, none of whom responded to treatment. - The disease control rate achieved with ERBITUX monotherapy was also considerably higher than that seen in the retrospective study (46% versus 15%). - ERBITUX monotherapy demonstrated an overall survival of 5.9 months, which is outstanding for this population of patients. - The overall survival achieved with ERBITUX represented an absolute increase of 2.5 months in overall survival compared with the retrospective study. - Interestingly, as shown by the data from the other two prospective ERBITUX studies, the efficacy, in terms of both response and survival, achieved with ERBITUX monotherapy was not improved by the reinclusion of platinum in the regimen. 1. Vermorken JB, Bourhis J, Trigo J, et al. J Clin Oncol 2005;23(16S):Abstract Virtual presentation: Vermorken et al. J Clin Oncol 2005;23(16S):Abstract 5505 Virtual presentation:

13 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 - 总生存期
爱必妥单药治疗 爱必妥/ 顺/卡铂 爱必妥/ 顺铂 回顾性分析 (所有患者) 分析的局限性: 使用了历史对照组 Vermorken. J B, ASCO 2005

14 爱必妥™ + platinum 和单独使用爱必妥™的临床疗效比较
中位 OS 中位 TTP 6.1 5.9 5.2 时间（月） 3.4 2.8 2.3 2.2 NA 爱必妥1 爱必妥 + CDDP/ carboplatin2 爱必妥 + CDDP3 回顾性分析 (所有患者)4 1Trigo, et al. J Clin Oncol 2004;22(Suppl. 14s):488s [Abstract No. 5502]; 2Baselga, et al. J Clin Oncol 2005;23:5568–5577; 3Herbst, et al. J Clin Oncol 2005;23:5578–5587; 4Leόn, et al. Clin Oncol (R Coll Radiol) 2005;17:418–424

15 爱必妥TM相关的3/4级不良反应 不良反应 爱必妥 单药治疗 (n=103) 呼吸困难 痤疮样皮疹 超敏反应 4% 1%
Trigo J, et al. J Clin Oncol 2004;22(Suppl. 14s):488s [Abstract No. 5502]

16 爱必妥用于一线治疗失败 R&M SCCHN的荟萃分析 - 总结
3项爱必妥研究证实了一致的中位生存期(5.2–6.1 个月) 在铂类失败的R&M SCCHN患者中，与爱必妥单用相比，联合铂类治疗未带来额外的获益 爱必妥耐受性良好，且未加重铂类治疗的副反应 - The results from this analysis in patients with recurrent and/or metastatic SCCHN progressing on prior platinum therapy show that the relatively long median overall survival of nearly 6 months observed with ERBITUX monotherapy represented an absolute increase of 2.5 months compared with other second-line therapies. - Consistent median overall survival times of months were seen in three ERBITUX studies. - Interestingly, the reintroduction of platinum conferred no additional efficacy benefit over ERBITUX monotherapy. - Although this analysis is limited by the use of a retrospective study as a comparator, it is indicative of the benefits of ERBITUX in this poor prognosis group of patients who have failed platinum-based chemotherapy and have no further standard treatment options. 1. Vermorken JB, Bourhis J, Trigo J, et al. J Clin Oncol 2005;23(16S):Abstract Virtual presentation: Vermorken et al. J Clin Oncol 2005;23(16S):Abstract 5505 Virtual presentation:

17 爱必妥用于铂类治疗失败的R&M SCCHN : 总结
6 个月的中位生存期 爱必妥 铂类失败后 50% 的疾病控制率 卓越的安全性

18 爱必妥联合以铂类为基础的治疗 Progress under platinum October 15, 1998
Post-treatment with 1 cycle of ERBITUX + platinum November 9, 1998 Shin DM, et al. Clin Cancer Res 2001;7:1204–1213

19 爱必妥用于化疗失败的鼻咽癌 (NPC)

20 一项关于西妥昔单抗联合卡铂用于 铂类治疗失败的复发转移性鼻咽癌的 多中心II期临床研究
Chan AT, Hsu MM,Goh BC, Hui EP, Liu TW, Millward MJ, Hong RL, Whang-Peng J, Ma BB, To KF, Mueser M, Amellal N, Lin X, Chang AY - Nasopharyngeal carcinoma (NPC) is a distinct form of cancer which develops from the epithelial cells that comprise the surface lining of the nasopharynx. - EGFR is highly expressed in patients with NPC (up to 94%) and has been shown to be an independent predictor of poor clinical outcome in this disease.[1] - Activity against NPC has been observed in pre-clinical models with specific inhibitors of the EGFR family.[2] - Several studies in head and neck cancer patients suggested ERBITUX acts synergistically with platinum analogues.[3-5] - This phase ll study was carried out to evaluate the activity and safety of ERBITUX plus carboplatin in patients with recurrent and/or metastatic NPC who had experienced treatment failure on platinum-based therapy.[3] 1. Ma BB, Poon TC, To KF, et al. Head Neck 2003;25: 2. Sun Y, Fry DW, Vincent P, et al. Anticancer Res 1999;19: 3. Chan AT, Hsu MM, Goh, BC, et al. J Clin Oncol 2005;23: 4. Herbst RS, Arquette M, Shin DM et al. J Clin Oncol 2005;23: 5. Baselga J, Trigo JM, Bourhis J et al. J Clin Oncol 2005;23: Chan et al. J Clin Oncol 2005;23:

21 爱必妥联合卡铂用于 NPC 背景 NPC为亚洲和北非最为常见的头颈部癌，发病率为15-50 /100,000 对放疗和化疗非常敏感:
对于早期病例放疗适主要的治疗手段 放化疗联合用于局部晚期患者 晚期患者局部复发和远处转移率高，预后不良 对于这部分患者的治疗需求尚未被满足 - In many parts of Asia and North Africa, NPC is the most common head and neck cancer with an incidence of per 100,000.[1] - NPC is highly radiosensitive and chemosensitive and the primary treatment for early stage disease is radical radiotherapy.[2] Locally advanced disease is treated with combined chemotherapy-radiotherapy.[2] - Advanced disease is associated with significant rates of local recurrence or distant metastasis.[3-5] - For patients with distant metastasis, the prognosis is poor, with reported median survival times ranging from 5 to 11 months.[3-5] There is an unmet need for new treatments for patients at this stage of their disease. 1. Chan AT, Hsu MM, Goh, BC, et al. J Clin Oncol 2005;23: 2. Chan AT, Teo PM, Johnson PJ. Cancer Treat Res 2003;114: 3. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles and Practice of Oncology.Vol. 1. Philadelphia: Lippincott Williams and Wilkins, 2001:3235. 4. Hui EP, Leung SF, Au JS, et al. Cancer 2004;101: 5. Geara FB, Sanguineti G, Tucker SL, et al. Radiother Oncol 1997;43:53-61 Chan et al. J Clin Oncol 2005;23: 1 1 1 1

22 治疗直至出现疾病进展或毒性不可耐受或达到最大治疗周期数 ( 8 )
爱必妥联合卡铂用于 NPC -研究设计 入组患者 n=60 21天为一个治疗周期: 爱必妥 首剂 400 mg/m2 ,之后每周250 mg/m2 卡铂 AUC 5 治疗直至出现疾病进展或毒性不可耐受或达到最大治疗周期数 ( 8 ) - A total of 60 patients were enrolled to this single arm study in 6 centers. - All patients received ERBITUX at an initial dose of 400 mg/m2 in a 2-h infusion. - ERBITUX was subsequently administered at weekly doses of 250 mg/m2 over 1-h. - Carboplatin, with a targeted AUC of 5, was administered after the ERBITUX infusion on day 1 of a 21-day treatment cycle. - Treatment continued until disease progression, unacceptable toxicity or up to a maximum of 8 cycles. - If patients had not progressed by this stage, treatment with ERBITUX monotherapy could be administered until disease progression. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: 若患者仍未出现疾病进展 爱必妥单药治疗直至 PD Chan et al. J Clin Oncol 2005;23:

23 爱必妥联合卡铂用于 NPC - 患者入组标准 组织学证实的复发或转移性 NPC 在最后一次铂类为基础的治疗结束后12个月内疾病进展
病灶可测量 (RECIST 标准) KPS > 60% 足够的骨髓、肝、肾功能 - Patients were eligible for inclusion in this study if they had: -- histologically proven, recurrent and/or metastatic NPC -- documented progression on or within 12 months after the end of treatment with platinum-based chemotherapy for recurrent and/or metastatic disease -- measurable disease according to RECIST criteria by CT scan or MRI -- Karnofsky performance status of >60% -- adequate bone marrow, hepatic and renal function. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: RECIST=Response Evaluation Criteria in Solid Tumors Chan et al. J Clin Oncol 2005;23:

24 爱必妥联合卡铂用于 NPC - 研究终点 主要终点: RR 次要终点: TTP 疗效持续时间 总生存 安全性
- The primary endpoint for this study was response rate. - The secondary endpoints were: -- time to response -- duration of response -- time to progression -- overall survival -- safety. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: Chan et al. J Clin Oncol 2005;23:

25 AJCC=American Joint Committee on Cancer
爱必妥联合卡铂用于 NPC - 患者特征 患者特征 (1) n=60 性别: M / F 46 / 14 中位年龄 (years) 44.5 人种, 中国 (%) 93 KPS (%) 90 入组时的肿瘤分期 (AJCC) (%) Stage IV M1, metastases 85 患病时间 (months) 24.2 - Of the 60 enrolled patients, 46 (77%) were male and the median age was 44.5 years. - The majority of patients were Chinese. - The median Karnofsky performance status was 90%. - The majority of patients (93%) had stage IV disease. Among these patients, 85% had distant metastasis. - The median duration of disease at time of enrolment on the study was 24.2 months. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: AJCC=American Joint Committee on Cancer Chan et al. J Clin Oncol 2005;23:

26 爱必妥联合卡铂用于 NPC - 治疗特征 治疗特征 % (n=60) 既往姑息性化疗的线数 1 line 2 lines 3-6 lines
70 13 17 最近一次的化疗方案 cisplatin cisplatin combination carboplatin combination paclitaxel docetaxel gemcitabine vinorelbine 12 38 45 20 2 15 7 - 70% of patients had received one prior line of palliative chemotherapy, 13% had received two lines and 17% had received three - six lines before treatment with ERBITUX. - The majority of patients had received prior platinum treatment: 12% with cisplatin, 38% with a cisplatin combination and 45% with a carboplatin combination. - Several other agents had also been used, with 20% of patients receiving prior paclitaxel, 2% receiving docetaxel, 15% receiving gemcitabine and 7% receiving vinorelbine. - Altogether, most patients had received between two and five different agents, with some patients having had exposure to eight different compounds. - In addition, 88% of patients had received radiotherapy prior to enrolment. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: 既往放疗 88 Chan et al. J Clin Oncol 2005;23:

27 爱必妥联合卡铂用于铂类治疗失败的 NPC 有效
疗效 % (n=60) PR 12 SD 48 ORR Disease control 60 Overall survival 7.7 months - Seven patients (12%) had a partial response and a further 29 patients (48%) had stable disease. - Thus, the overall response rate was 12% and the disease control rate was 60%. - The median overall survival was 7.7 months. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: Chan et al. J Clin Oncol 2005;23:

28 爱必妥联合卡铂用于铂类治疗失败的 NPC 耐受性良好
3/4 级副反应 % (n=60) 贫血 18 痤疮样皮疹 12 呼吸困难 血小板减少 10 虚弱 8 呕吐 7 神经痛 胸膜渗出 5 低钾血症 吞咽困难 肌无力 肺炎 感染 粒细胞减少 - ERBITUX plus carboplatin was well tolerated in this population. - Grade 3/4 adverse events were reported by 52% of patients, and in 32% of patients these were assessed as ERBITUX-related. - The most common grade 3/4 adverse events were: -- anemia 18% -- acne-like rash 12% -- dyspnea 12% -- thrombocytopenia 10%. - Other grade 3/4 adverse events were reported in less than 10% of patients. - Skin reaction are commonly associated with EGFR inhibitors, including ERBITUX. The other side effects were thought to be associated with the underlying disease or were recognized side effects of carboplatin treatment. - ERBITUX did not increase the adverse events typically associated with carboplatin. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: Chan et al. J Clin Oncol 2005;23:

29 爱必妥联合卡铂用于 NPC - 结论 爱必妥用于铂类治疗失败的NPC有效 ORR 12% 疾病控制率 60% 中位生存 7.7 个月
爱必妥联合卡铂耐受性良好 - ERBITUX plus carboplatin has demonstrated important clinical benefit in patients with recurrent/metastatic NPC who had failed platinum therapy. - The activity of the ERBITUX plus carboplatin combination was particularly remarkable as many of the patients were heavily pretreated. - An overall response rate of 12% was achieved, with a disease control rate of 60% and median survival of 7.7 months. - The combination of ERBITUX plus carboplatin was also well tolerated. 1. Chan AT, Hsu MM, Goh BC, et al. J Clin Oncol 2005;23: Chan et al. J Clin Oncol 2005;23:

30 Thanks!