爱必妥联合放化or化疗食道癌2010ASCO.ppt

1、爱必妥治疗食道癌2010ASCO更新,概述,食道癌占全球癌症死因第6位 亚洲国家常见病理类型：鳞状细胞癌 西方国家常见病理类型：腺癌 50-80的食道癌有EGFR表达,C-225联合同步放化疗治疗胃食道癌,治疗方案： C-225：400mg/m2（第1周），250mg/m2（第2-6周） 紫杉醇：50mg/m2/w + 卡铂 AUC2/w（第1-6周） 同步放疗：DT 50.4Gy/28F Safran H,et al. Int.J.Radiat Oncol Biol Phys. 2007.10,一项II期临床初步结果,爱必妥+紫杉醇+顺铂+放疗，用于局部晚期食道鳞癌 治疗时间7周 39例入组

2、，32例完成计划，CR15例，PR15例，SD1例， 有1例未评估 有效率RR为93.8% K-ras均为野生型 结论此爱必妥+放化疗方案治疗食道癌，耐受性好，有效率达预期，毒性可预测,爱必妥+放化疗用于食道癌新辅助,术前爱必妥200mg/m2/周+放化疗，术后再用4-6周， 共用16周 15例入组，7例R0切除（4例CR，1例PR，2例SD） 3例经影像学及内镜证实CR，但无手术指证 8/15有效，2年无复发率40%（6/15） 另有3例一年无复发,爱必妥为基础的新辅助化疗在食道癌和胃癌提高手术切除率,55例食道癌，5例胃癌 爱必妥+PC方案（紫杉醇+卡铂）每周6 57例患者完成治疗，44例

3、手术，13例内镜下重分期， （6例不能手术，7例减瘤） 常见毒性有食道粘膜炎、皮疹等 内镜证实的CR22%，接近CR22%（残余癌镜下1个）， PR25%，SD30% 20例降期 爱必妥为基础的新辅助显著降期，提高切除率，毒性有限,爱必妥+放化疗治疗局晚不可切除食道癌（SWOG0414）,爱必妥+CPT-11+顺铂+放疗的方案 22例入组，17例可评价，1例CR，2例PR，3例SD 2例死亡（猝死和消化道坏死） 3级毒性48%，4级29%，主要有血红蛋白下降、疲劳、腹泻、恶心呕吐、脱水、厌食 验证了入组病人的基因表达与其预后无相关性 结论耐受性较差，但是初步结果令人鼓舞，因此，SWOG赞同进行

4、RTOG 0436研究，进一步确定西妥昔单抗能够作为食道癌基础用药。,爱必妥治疗食管癌,治疗模式有同步放化疗、新辅助爱必妥+化疗、新辅助爱必妥+放化疗 小样本初步结果令人鼓舞 最合适的治疗模式有待进一步研究 安全性有待进一步观察,爱必妥+FOLFOX治疗III期贲门及食道癌研究的中期分析,有效率RR 28/36（66%），其中14例CR，14例PR，另5例SD 18例失访的病人中14例一个月以上无进展 主要毒性粘膜炎、呕吐、中性粒细胞减少伴发热、吞咽困难、过敏 初步结果表明爱必妥+FOLFOX方案安全、有效，支持试验入组到计划的80例。,爱必妥+紫杉醇+顺铂+放疗，放疗达到40Gy后，评价是否

5、可手术切除，如不可切除，则放疗至60-66Gy 41例入组，20例手术，9例接受放疗至60-66Gy ITT人群的CR26%，随访10.3月，一年PFS率69%，OS率66%， 主要的3/4级毒性是白细胞减少、中心粒细胞减少、食道炎、 感染、皮疹、低镁血症。 结论此爱必妥联合方案是安全有效的。,爱必妥+放化疗治疗局部晚期食道鳞癌,爱必妥为基础的治疗食道腺癌研究（E2205）,爱必妥+奥沙利铂+5-Fu术前新辅助，术后继贯爱必妥+多西紫杉醇的治疗，观察有效率和毒性 22例入组，18例手术，pCR的7例，13/18进行术后辅助化疗，12例完成（停止试验的由于放化疗后肺栓塞死亡、3腹泻死亡、败血症死

6、亡） 总共有7例死亡，4例由于ARDS（成人呼吸窘迫症），有2例pCR的也死于此 结论是有希望提高pCR率，毒性导致I期试验后终止。 所有术后死亡都由于ARDS，死因正在研究。 此方案不做推荐,爱必妥+化疗治疗转移性食道癌及胃食道结合部癌（CALGB80403/ECOG1206）,爱必妥分别+ECF/IC/FOLFOX治疗， ECF组和FOLFOX组都有超过40%的有效率，ECF组的更高，（58% VS 51%），IC组最低为38%。 FOLFOX组的毒性更低,结论,C-225联合紫杉醇、卡铂的同步放化疗治疗胃食道癌患者是安全的 C-225会增加皮肤毒性和过敏反应的发生率 C-225最突出的皮

7、肤毒性反应表现为：颜面部疼痛、掻痒的痤疮样皮疹，其他常见的部位包括胸部和腹部 放疗区域皮肤的皮疹并没有加重 皮疹在治疗的第1-3周最为严重 口服强力霉素、头孢氨苄可用于治疗皮疹,An open label, multicenter clinical study of cetuximab combined with concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Preliminary results of a phase II trial.,J Clin Oncol 28

8、, 2010 (suppl; abstr e14520) Author(s): J. M. Yu, J. H. Wang, X. Sun, L. H. Wang, G. Y. Zhu, P. B. Feng, M. Ye, Y. Lu, S. C. Zhu, Z. X. Liao; Shandong Cancer Hospital and Institute, Jinan, China; Henan Cancer Hospital, Zhengzhou, China; Cancer Hosptial, Chinese Academy of Medical Science, Peking Uni

9、on Medical College, Beijing, China; Beijing Cancer Hospital and Institute, Beijing, China; Jiangsu Cancer Hospital, Nanjing, China; Renjin Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China; Department of Thoracic Oncology, State Key Laboratory of Biotherapy, Huaxi Hospital, Sichua

10、n University, Chengdu, China; Fourth Hospital, Hebei Medical University, Shijiazhuang, China; University of Texas M. D. Anderson Cancer Center, Houston, TX,Methods:,Patients aged 18-70 years with stage II-III cervical, upper thoracic and midthoracic locally advanced nonresectable ESCC, ECOG performa

11、nce status (PS) 1 received cetuximab (400 mg/m2 on day1 before chemo-radiotherapy and then q1w7 weeks) plus paclitaxel (45 mg/m2 q1w7 weeks) and cisplatin (20 mg/m2 q1w7 weeks). Radiotherapy consisted of 59.4 Gy in 33 fractions in 7 weeks. The primary endpoint was overall response rate and secondary

12、 endpoints included time to disease progression, overall survival at 1 year and 3 year, toxicity and K-ras status. Planned accrual was 44 patients.,Results:,.Preliminary data are available for 39 patients, including 31 male and 8 female. Median age was 58 years old. 32 of all included patients finis

13、hed the planned treatment. The overall response rate was 93.8% (complete response, n = 15; partial response, n = 15). Stable disease was observed in 1 patient, and 1 patient has not been evaluated. The most relevant NCI-CTC grade 3 hematologic events were neutropenia (12.8%), febrile neutropenia (5.

14、1%), and anemia (2.5%). Major nonhematologic toxicities were acneiform skin eruptions ( grade 2 in 17.9% of patients) and dermatitis (64.1%). The acneiform skin eruptions mainly started at the third week of cetuximab treatment. At the fourth week of radiotherapy, 15.3% and 25.6% of the patients bega

15、n to suffer from grade 1-2 dermatitis and mucositis, respectively. No grade 4 adverse event was observed. The K-ras status of all patients was wild-type genetype.,Conclusions:,The combined treatment modality of cetuximab plus concurrent chemoradiotherapy in locally advanced ESCC in China were well t

16、olerated and resulted in promising response rates and a predictable toxicity profile.,High complete response (CR) rate and 2-year survival rates with no evidence of disease (NED) in patients (pts) with esophageal carcinoma (EC) undergoing neoadjuvant combination of docetaxel and cisplatin (DC) cetux

17、imab (DCE) chemoradiation therapy,2008 Gastrointestinal Cancers Symposium Session Type and Session Title: General Poster Session B Abstract No:121 Author(s): T. J. Fillos, P. Hentschel, K. T. Watkins, M. S. Karpeh, A. Meek, B. Kim, D. Franceschi, S. Zee, S. Madajewicz,Methods:,Newly diagnosed pts wi

18、th EC Stage 2A (T3) to 4 received weekly Docetaxel (D) 25- 30 mg/m2 and Cisplatin (C) 25-30 mg/m2 for 6-8 weeks concurrently with radiation, 5,040 cGy in 28 fractions. Cetuximab (E) 200 mg/m2 Pts were scheduled 4 - 6 weeks later for surgery followed by the same chemotherapy for total of 16 weeks of

19、treatment. Pts were assessed for time to progression, overall survival and toxicities.,Results:,Fifteen pts treated in 2005-2006 underwent IRB approved evaluation; 11 male and 4 female, median age of 62 (range 44-78). Four had squamous cell (SCC) and 11 adenocarcinoma. Thirteen pts had stage IIa to

20、III and 2 pts stage IV disease. Seven underwent R0 resections with 4 pCR and 1 pPR and 2 stable disease. Five progressed prior to surgery. Three pts (one with metastatic disease) had radiological and endoscopic proven CR but medically were not surgical candidates. A total of 8 pts out of 15 experien

21、ced RR (7 CRs and 1 PR -53%). Six out of 15 patients (40%) remain alive with NED after 2 years. An additional 3 pts have NED after 12 months.,Cetuximab-based neoadjuvant chemoradiation appears to facilitate surgical resection in patients with locally advanced esophageal and gastric cancer.,2008 Gast

22、rointestinal Cancers Symposium Session Type and Session Title: General Poster Session A Abstract No:33 Author(s): H. J. Wanebo, T. DiPetrillo, T. Kennedy,Methods:,Patients with locally advanced endoscopically and radiologically staged esophageal (55) and gastric cancer (5) (T2-4, N1-3, M0) were enro

23、lled in an IRB approved protocol including cetuximab 400 mg/M2 week 1, then 250 mg/M2/week x 5, paclitaxel 50mg/M2/week and carboplatin AUC = 2 weekly x 6 with concurrent 50.4 Gy.,Results:,Fifty seven evaluable patients (50 M/7 F, median age 58 yrs) completed neoadjuvant therapy: 44 had surgery,13 h

24、ad restaging endoscopy only (6 were inoperable and 7 declined surgery). Major toxicities were esophageal mucositis (grade 3/4 in 10 pts 20%, grade 3 dehydration in 5 pts, rash in 20 pts, and drug hypersensitivity in 2 pts) An endoscopically confirmed complete response was shown in 28 of 44 surgical

25、pts (64%) and in 10 of 13 having endoscopy only. Major resections included Ivor Lewis (thoracoabdominal +/-cervical reconstruction 30 pts, transhiatal resection 12 pts and gastrectomy 2 pts). There was 1 post operative death. Significant primary site downstaging occurred in 20 pts (42%) with final s

26、tage T0 (N0 (8), T0N1-3(3),T1 N0 (7), T1N1 (2). Surgical pathology included: complete path response (no residual cancer) in 10 pts (22%), a near CR (residual 1 microscopic foci only) in 10 pts (22%), partial response (50% regression) in 11 pts (25%) and persistent residual cancer in 13 pts (30%).,Co

27、nclusion:,Cetuximab-based neoadjuvant chemoradiation for locally advanced esophageal and gastric cancer is tolerable, has limited toxicity and appears associated with significant downstaging facilitating surgical resection in the majority of patients.,Cetuximab plus cisplatin, irinotecan, and thorac

28、ic radiotherapy (TRT) as definitive treatment for locally advanced, unresectable esophageal cancer (EC): A SWOG (S0414) phase II trial.,2010 Gastrointestinal Cancers Symposium Session Type and Session Title: General Poster Session A: Cancers of the Esophagus and Stomach Abstract No:72 Author(s): C.

29、R. Thomas Jr., B. H. Goldman, J. K. Benedetti, H. Lenz, T. Beeker, J. L. Abbruzzese, C. Blanke; Oregon Health University of British Columbia/British Columbia Cancer Agency, Vancouver, BC, Canada,Objective,a phase II trial (S0414) to test a novel CRT approach of cetuximab, cisplatin, irinotecan, and

30、TRT. Specific aims were to determine: 1) 2-yr overall survival (OS) 2) toxicity 3) response rate 4) progression-free survival (PFS) 5) association between gene expression levels and germline polymorphisms involved in DNA repair, drug metabolism, EGFR pathway, and clinical outcome,Methods:,Eligibilit

31、y: cT4M0 stage or medically unresectable, biopsy-proven, EC (squamous cell or adenocarcinoma). Cetuximab 400 mg/m2 was given day (d) 1 of cycle (C) 1, then 250 mg/m2 was given d8, 15 of C1 and d1, 8, 15 for subsequent C; cisplatin 30 mg/m2 was given d1, 8 each C; irinotecan 65 mg/m2 was given d1, 8

32、each C. TRT started d1 C3 at 1.8 Gy/d x 28 fxs, 5 d/wk to total dose 50.4 Gy. Planned accrual was 75 adeno pts and 25 squamous cell pts, with the regimen considered of further interest if 2-yr OS 43%.,Results:,22 pts enrolled :1 pt was ineligible (tumor 20 cm from incisors). M/F = 15/6, Zubrod PS 0-

33、1 = 20, 2 = 1; Adeno/Squam = 10/11, White/Non-white = 15/6, med. age 61 yrs. 2 deaths occurred on protocol (sudden death and GI necrosis); 6 pts had Gr 4 toxicities. 48% and 29% of pts had Gr 3 and 4 toxicity, respectively: 52% heme, 24% fatigue, 24% diarrhea, 19% nausea/emesis, 19% dehydration, and

34、 19% anorexia. 17 pts were evaluable for RECIST response, including 1 CR (6%), 2 PR (12%), and 3 Stable (18%). Med. PFS = 6.4 mos and OS = 11.2 mos after 30 mos follow-up. Gene expression levels were available for 17 pts. No significant associations between marker expression and outcome were observe

35、d.,Conclusions:,Concomitant cetuximab, cisplatin, irinotecan, and TRT for pts with EC were poorly tolerated in the first cooperative group trial with this regimen. Single-institution phase II cetuximab-based CRT has yielded encouraging preliminary results. Hence, SWOG endorses RTOG-0436 to further d

36、efine the therapeutic ratio of cetuximab-based CRT for EC.,ERaFOX Trial,Chemoradiation with FOLFOX plus cetuximab in stage III cardia or esophageal cancer: Interim analysis from a GERCOR phase II trial (ERaFOX),2010 Gastrointestinal Cancers Symposium Session Type and Session Title: General Poster Se

37、ssion A: Cancers of the Esophagus and Stomach Abstract No: 68 Author(s): G. Lledo, P. Michel, O. Dupuis, J. F. Seitz, L. Mineur, M. P. Galais, B. Chibaudel, N. Jovenin, A. de Gramont; Hpital Priv Jean Mermoz, Lyon, France; Universitary Hospital, Rouen, France; Clinique Victor Hugo, Le Mans, France;

38、C.H.U. la Timone, Marseille, France; Institut Sainte-Catherine, Avignon, France; Centre Rgional Franois Baclesse, Rouen, France; GERCOR, Paris, France; Institut Jean Godinot, Reims, France; CHU Saint-Antoine, Paris, France,Methods:,Main inclusion criteria were: stage III squamous cell or adenocarcin

39、oma of the esophagus or gastroesophageal junction; WHO PS 0-1; age 18-80 years; weight loss 15% in the last 6 months. Patients (pts) received 2 cycles of induction FOLFOX plus cetuximab therapy, then 50.4Gy of radiation with FOLFOX plus cetuximab. Tumor evaluation was performed at the end of CRT. Pr

40、imary end-point was the overall response rate (ORR, RECIST).,Results:,male/female 24/12, median age 63 years (23-79), PS 0/1/ND 22/13/1, squamous/adenocarcinoma/undifferentiated 20/15/1; esophagus/cardia 32/4; median daily caloric intake 1720 Kcal (1115-2551). 35 pts were treated by CRT (one pt expe

41、rienced G4 allergy during the first cetuximab infusion). ORR was achieved in 28 pts (CR/PR: 14/14; 10 confirmed response), 5 pts had stable disease, and 1 pt had disease progression (2 pts were not evaluable). Among 18 patients with unconfirmed tumor response, 14 had no PD 1 month after evaluation;

42、ITT ORR of 66.6% (24/36). Grade 3/4 toxicities induction therapy/CRT (%): neutropenia: 0/17.1; febrile neutropenia: 0/2.9; vomiting: 2.8/0; mucitis: 2.8/2.9; diarrhea: 5.6/2.9; dysphagia-esophagitis: 2.9/2.9; rash: 8.3/5.7; allergy 2.8/0.,Conclusions:,Preliminary analysis suggests that CRT with FOLF

43、OX-cetuximab is safe and active in cardia or esophagus cancer, supporting continuation of the study until the planned accrual of 80 pts.,Concurrent chemoradiotherapy with cetuximab plus twice weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal squamous cell carc

44、inoma.,2010 ASCO Annual Meeting Session Type and Session Title: General Poster Session, Gastrointestinal (Noncolorectal) Cancer Abstract No: 4106 Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr 4106) Author(s): C. Hsu, C. Lin, J. C. Cheng, C. Yen, J. Lee, H. Wang, K. Yeh, A. Cheng, Y. Lee; Departm

45、ent of Oncology, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University Hospital, Taipei, Taiwan; Taipei Veterans General Hospital, Taipei, Taiwan,Methods:,Patients with operable ESCC (T3N0-1M0 or T1-3N1M0 or M1a) treated with paclitaxel (35 mg/m2 1 h on days 1 and 4/week),

46、cisplatin (15 mg/m2 1 h on days 2 and 5/week), cetuximab (400 mg/m2 2 h on day -5, then 250 mg/m2 2 h on day 3/week) and radiotherapy (2 Gy on days 1-5/week) When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated for all patients. patients for whom esophage

47、ctomy was not feasible, CCRT was continued to a radiation dose of 60-66 Gy.,Results:,Forty-one patients with ESCC were enrolled, and the majority had T3N1M0 or M1a tumors by endoscopic ultrasonographic staging (95%). All patients received CCRT to 40 Gy. Twenty patients underwent surgery, and 9 patie

48、nts continued definitive CCRT to 60-66 Gy. Of the scheduled doses of paclitaxel, cisplatin, and cetuximab, 77%, 77%, and 98% were given, respectively. The intent-to-treat pathological complete response rate was 26% (8/31) (95% confidence interval: 9%-51%). At the median follow-up of 10.3 months, the

49、 projected one-year progression-free and overall survivals were 69% and 66%, respectively. The most common grade 3/4 toxic effects were leukopenia (64%), neutropenia (18%), esophagitis (9%), and infection (9%). Grade 1, 2, and 3 skin rash occurred in 58%, 30%, and 3% of patients, respectively. Grade

50、 1, 2, 3, and 4 hypomagnesemia occurred in 15%, 6%, 0%, and 6% of patients, respectively.,Conclusions:,Adding cetuximab to twice-weekly paclitaxel/cisplatin-based CCRT prior to esophagectomy is an active and safe treatment for locally advanced ESCC.,E2205: A phase II study to measure response rate a

51、nd toxicity of neoadjuvant chemoradiotherapy (CRT) with oxaliplatin (OX) and infusional 5-fluorouracil (5-FU) plus cetuximab (C) followed by postoperative docetaxel (DT) and C in patients with operable adenocarcinoma of the esophagus.,2010 ASCO Annual Meeting Session Type and Session Title: General

52、Poster Session, Gastrointestinal (Noncolorectal) Cancer Abstract No:4064 Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr 4064) Author(s): M. K. Gibson, P. J. Catalano, L. Kleinberg, C. A. Staley, E. Montgomery, W. Song, M. F. Mulcahy, L. P. Leichman, A. B. Benson; University of Pittsburgh Cancer I

53、nstitute, Pittsburgh, PA; Dana-Farber Cancer Institute, Boston, MA; The Johns Hopkins University, Baltimore, MD; Emory Clinic, Atlanta, GA; Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; Pottstown Cancer Center, Pottstown, PA; Northwestern University Feinberg School of Medicine, Chi

54、cago, IL; Comprehensive Cancer Center at Desert Regional Medical Center, Palm Springs, CA,Methods:,We aimed to increase the pathologic complete response (pCR) rate from 25% to 45%. A Simon two-stage design ( and of 0.10) required pCR/enrolled of 5/18 for stage I and 14/40 total. 22 pts enrolled. CRT

55、: OX 85 mg/m2 D1, 15, 29; infusional 5-FU 180 mg/m2/24 hr x 35 days; C 400 mg/m2 D1 then 250 mg/m2 D8, 15, 22, 29 and radiation (IMRT allowed) 180 cGy/day x 25 fractions (M-F). Following esophagectomy, adjuvant chemotherapy (CT): weekly DT 35 mg/m2 and C 250 mg/m2 5/6 weeks x 2 cycles. Endpoints: ef

56、ficacy by pCR rate and toxicity.,Results:,Of 22 patients enrolled, 18 had surgery (C reaction off study, died PE 4 days after CRT, G3 diarrhea during CRT died disease progression, died sepsis/hypoxia during CRT). pCR = 7 patients. 13/18 started adjuvant CT. 12/13 completed adjuvant CT. Four post-op

57、deaths, all from ARDS, for a total of 7 deaths on study. 2/7 pts with pCR died, both of ARDS. With small numbers, the use of IMRT did not correlate with ARDS, but analysis of dosimetry is ongoing. Data updated 010610.,Conclusions:,This regimen demonstrated promising activity based on pCR rate. Toxicity was significant, leading to closure after stage I. All post-op deaths were due to ARDS. Investigation of ARDS cause is ongoing. Correlative studies underway. Th