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特罗凯治疗胰腺癌
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特罗凯治疗胰腺癌 （PI）
In Brief简介
· & & & The safety and efficacy of Tarceva in combination with gemcitabine as a first-line treatment in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer have been demonstrated in a multinational, randomized, double blind, placebo-controlled Phase III trial.厦门174医院肿瘤科陈建清
· & & & 多中心随机双盲安慰剂对照 III 期试验证明了特罗凯联合吉西他滨作为一线治疗方案治疗 569 名患有局部晚期、不可切除或转移性胰腺癌患者的安全性和疗效。
· & & & The addition of Tarceva to gemcitabine significantly extended survival in pancre the hazard ratio (HR) was 0.81 (p=0.028), indicating:
· & & & 吉西他滨联合特罗凯治疗显著地延长了胰腺癌患者的存活期；风险比 (HR) 为 0.81 (p=0.028)，表明：
o&&&&&&& An 19% ([1-0.81] x 100%) reduction in the risk of death in patients treated with Tarceva compared with placebo.
o&&&&&&& 与接受安慰剂治疗的患者相比，接受特罗凯治疗的患者的死亡危险降低了 19%([1-0.81] x 100%)
o&&&&&&& A 23% ([1/0.81 - 1] x 100%) improvement in overall survival with the combination of Tarceva plus gemcitabine as compared to gemcitabine alone.
o&&&&&&& 与仅接受吉西他滨治疗的患者相比，接受特罗凯联合吉西他滨治疗的患者的总存活率提高了 23% ([1/0.81 - 1] x 100%)
·&&&&&&&& The recommended dose of Tarceva, in combination with gemcitabine, in pancreatic cancer patients is 100 mg daily.& Tarceva should be taken at least 1 hour before or 2 hours after the ingestion of food.& Treatment should continue until disease progression or unacceptable toxicity occurs.
· & & & &特罗凯联合吉西他滨治疗胰腺癌患者的方案中，特罗凯的推荐剂量为 100 毫克/天。至少在饭前1小时或饭后2小时服用。持续用药直到疾病进展或出现不可耐受的毒性反应。
· & & & &In the pivotal trial, commonly reported adverse events include rash, diarrhea, anorexia, the majority of these events were mild to moderate in severity. &
· & & & &在关键性的试验中，通常报告的不良事件包括：皮疹、腹泻、食欲不振、恶心和疲劳；这些不良事件中大多数的严重度从轻度到中度。
· & & & &Infrequent cases of serious Interstitial Lung Disease (ILD)-like events, including fatalities, have been observed in patients receiving Tarceva.& In pancreatic cancer trials, the incidence of these events was 2.5% in the Tarceva group and 0.4% in the placebo group.
· & & & &接受特罗凯治疗的患者中观察到罕见的严重的间质性肺病（ILD）疑似事件，甚至导致死亡。胰腺癌试验中，特罗凯组中发生这些事件的比率为 2.5%，安慰剂组中此比率为 0.4%。
· & & & &Infrequent cases of myocardial infarction (MI)/ischemia and cerebrovascular accident, some with fatal outcomes, were observed in patients treated with Tarceva and gemcitabine.& In addition, cases of microangiopathic hemolytic anemia with thrombocytopenia were observed.& Tarceva is Pregnancy Category D.
· & & & &接受特罗凯联合吉西他滨治疗的患者中观察到罕见的心肌梗塞 (MI)/局部缺血和脑血管意外事件，一些导致死亡。此外还观察到血小板减少的微血管病性溶血性贫血事件。
Introduction介绍
Tarceva is a small molecule quinazolinamine that inhibits the intracellular phosphorylation of tyrosine kinase (TK) associated with EGFR.& The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines include the combination of Tarceva with gemcitabine as an acceptable treatment option for patients with locally advanced, unresectable or metastatic pancreatic cancer.1& More complete and detailed information may be found at www.nccn.org.&
特罗凯是一种小分子化合物，可抑制表皮生长因子受体 (EGFR) 酪氨酸激酶细胞内磷酸化。美国国家综合癌症网络 (NCCN) 临床实践指南将特罗凯联合吉西他滨纳入可接受的治疗方案，用于治疗局部晚期、不可切除或转移性胰腺癌患者。1 访问 www.nccn.org. 可获得更完整、更详细的信息。
Phase III Clinical Trial of Tarceva plus GemcitabineIII 期特罗凯联合吉西他滨的临床试验
The safety and efficacy of front-line Tarceva plus gemcitabine were evaluated in a multicenter, randomized, placebo-controlled, Phase III trial of 569 patients with locally advanced, unresectable and metastatic pancreatic cancer.2,3& The study was sponsored by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) at 176 sites in 18 countries.
多中心随机安慰剂对照组 III 期试验评估了特罗凯联合吉西他滨作为一线治疗方案治疗 569 名患有局部晚期、不可切除或转移性胰腺癌患者的安全性和疗效。2,3 该研究由加拿大国家癌病协会临床试验组(NCIC CTG) 开展，在 18 个国家 176 个地方进行。
Study Design研究设计
Eligible patients were randomized 1:1 to receive Tarceva or placebo once daily on a continuous schedule in combination with intravenous (IV) gemcitabine.& The majority of patients received 100 mg/day of Tarceva or placebo.& Interim safety analyses did not reveal any unexpected adverse events at the 100 mg dose level, and as such, open accrual to the 150 mg dose level at select study centers was allowed.& Due to rapid accrual in the 100 mg cohort, only 48 patients received 150 mg/day of Tarceva or placebo.& As such, too few patients were treated in the 150 mg cohort to draw conclusions.& This document focuses on results from the 100 mg/day cohort.& The study design is summarized in Figure&1.
符合条件的患者按 1:1 的比例随机安排持续接受特罗凯或安慰剂（每天一次）联合静脉注射 (IV) 的吉西他滨治疗。大多数患者接受剂量为 100 毫克/天的特罗凯或安慰剂。中期安全性分析并未显示剂量为 100 mg 时的意外的不良事件，同样，在选定的研究中心允许将剂量增加到 150 mg。接受 100 mg 治疗的患者越来越多，因此只有 48 名患者接受了剂量为 150 毫克/天的特罗凯或安慰剂。接受剂量为 150 毫克/天治疗的患者太少，因而不能能够得出疗效结论。本文件集中在剂量为 100 毫克/天的结果。图 1 中概括了研究设计。
Figure 1:& Study Design for Tarceva Pivotal Phase III Trial in Pancreatic Cancer2,3
Stratified by:
·&&&&&&&& Center
·&&&&&&&& ECOG PS (0/1 vs. 2)
·&&&&&&&& Stage of disease (locally advanced vs. metastatic)
Gemcitabine 1,000 mg/m2 IV†
Tarceva 100 mg
Gemcitabine 1,000 mg/m2 IV†
Placebo 100 mg
Gemcitabine 1,000 mg/m2 IV†
Tarceva 150 mg
Gemcitabine 1,000 mg/m2 IV†
Placebo 150 mg
†Gemcitabine Dosing Schedule
Cycle 1:& Days 1, 8, 15, 22, 29, 36 and 43 of 8-week cycle
Cycle 2 and beyond:& Days 1, 8 and 15 of 4-week cycle
Patients were treated until unmanageable toxicity or if related to oral or IV drug, the non-causal drug was continued until unmanageable toxicity or disease progression.
患者接受治疗直到出现难控制的毒性或疾病进展；如果与口服或静脉注射 (IV) 有关，继续接受无关联的药物直到出现难控制的毒性或疾病进展。
Study Endpoints研究终点
The primary efficacy endpoint was survival.2,3& Additional study endpoints included:& progression free survival (PFS), response rate (assessed by Response Evaluation Criteria in Solid Tumors [RECIST] criteria), duration of response (DR), quality of life (QoL) and safety.
主要疗效终点为存活期。2,3 其他的研究终点包括：无进展生存期 (PFS)、反应率（实体瘤反应评价[RECIST] 标准）、反应时期 (DR)、生活质量 (QoL) 和安全性。
Eligibility Criteria and Baseline Patient Characteristics合格标准和基线患者特征
Key eligibility criteria included:& histologically or cytologically confirmed pancreatic adenocarcinoma that was locally advanced, unresectable or metastatic, no prior chemotherapy other than 5-fluorouracil (5-FU) +/- folinic acid or gemcitabine given concurrently with radiation treatment as a radiosensitizer, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-2, and adequate hematology and biochemistry lab results.2,3& Patients were excluded from enrollment if they had history of malignancy within the last 5 years, significant cardiac disease, known CNS metastases, any prior epidermal growth factor receptor (EGFR) inhibitor therapy and/or significant gastrointestinal or ocular disorders.
关键的合格标准包括：组织学上或细胞学上确认的局部晚期、不可切除或转移性胰腺癌；除 5-氟尿嘧啶 (5-FU) +/- 亚叶酸或吉西他滨联合放射疗法作为放射增敏剂外，先前未接受化学疗法；美国东部肿瘤协作组 (ECOG) 体能状态 (PS) 评分 0-2；充分的血液学和生物化学实验结果。2,3 如果患者有以下情况，则不能入选，如在过去 5 年内有过恶性肿瘤病史、显著的心脏病、已知的中枢神经系统 (CNS) 转移、任一先前的表皮生长因子受体 (EGFR) 抑制剂治疗和/或显著的胃肠或眼睛疾病。
Patient baseline characteristics are summarized in Table 1.& Overall, baseline demographic and disease characteristics were similar between groups except for a slightly larger proportion of female patients in the Tarceva arm vs. the placebo arm.
表 1 中概述了患者基线特征。总的来说，两组间的基线人口统计学信息和疾病特征都相似，除了特罗凯组中女性患者比安慰剂组中略多之外。
Table 1:& Baseline Characteristics of Patients Enrolled in the Phase III Trial2
Characteristics
Tarceva + Gemcitabine
Placebo + Gemcitabine
Disease at Baseline
Locally Advanced
Distant Metastasis
a Unknown includes responses of \"Unknown\" and missing.
b Stratification factor as do distribution differs slightly from values reported at time of randomization.
Abbreviations:& ECOG PS=Eastern Cooperative Oncology Group Performance Status
Efficacy Results (100 mg cohort)疗效结果（100 mg 组）
Efficacy results for the pivotal pancreatic cancer trial are summarized in the following paragraphs.& In general, all randomized patients were included in the final intent-to-treat analysis for survival (primary endpoint).& Patients were evaluated every four weeks while on study and every 12 weeks post-treatment until death.& Those with at least one measurable lesion and at least one tumor assessment after baseline were ev patients with disease progression were also evaluable.&
以下段落中概述了关键性胰腺癌试验的疗效结果。总的来说，所有随机分组的患者包括在最终的意愿性治疗生存分析（主要终点）中。研究期间，每四周对患者进行评估，治疗后每 12 周对患者进行评估直到死亡。基线测量后，那些至少有一个可测量损伤或至少有一个肿瘤评估的患者可以评价反应；疾病进展的患者也可评价。
Survival存活期
The study met its primary endpoint by demonstrating a statistically significant improvement in overall survival (OS) in patients treated with Tarceva and gemcitabine compared with those receiving gemcitabine and placebo.2& Overall survival was defined as the length of time from randomization until death due to any cause.& The HR was 0.81 (p=0.028), indicating a 19% reduction in the risk of death in patients treated with Tarceva plus gemcitabine.& Alternatively, this corresponded to a 23% ([1/0.81 - 1] x 100%) improvement in OS with the combination of Tarceva plus gemcitabine as compared to gemcitabine alone.& The HR describes the overall risk of death in one treatment arm compared with the other arm over the entire time that patients are in a trial.& Median survival reflects one time point along the survival curve and does not measure the overall survival benefit.
与那些接受吉西他滨加安慰剂治疗的患者相比，接受特罗凯联合吉西他滨治疗的患者的总生存期 (OS) 有了显著地提高，因而研究达到了其主要终点。2 总生存期指的是从随机分组开始治疗开始直到由于任何原因死亡为止的一段时间。危害比 (HR) 为 0.81(p=0.028)，表示接受特罗凯联合吉西他滨治疗的患者的死亡危险降低了 19%。换句话说，与仅接受吉西他滨治疗的患者相比，接受特罗凯联合吉西他滨治疗的患者的总存活率提高了 23% ([1/0.81 - 1] x 100%)。危害比 (HR) 说明了与另一对照组相比，该治疗组总的死亡危险占患者在试验中总时间的比率。生存中值反映了生存曲线上的一个时间点，并不能测量总的生存期。
The median OS in the Tarceva and placebo groups were 6.4 months and 6.0 months, respectively (P=0.028).& The average time on treatment (start to last dose of therapy) was 18.5 weeks (range, 0.4 to 77.3+ weeks) in the Tarceva arm and 15.9 weeks (range, 0.1 to 77+ weeks) in the placebo arm.4
特罗凯组中中位总生存期 (OS) 为 6.4 个月，安慰剂组中中位总生存期为 6.0 个月(P=0.028)。特罗凯组中的平均治疗时间（治疗开始时剂量到最后的剂量）为 18.5 周（范围，0.4 至 77.3 + 周），安慰剂组中的平均治疗时间 15.9 周（范围，0.1 至 77 + 周）。4
Figure 2 depicts the Kaplan-Meier curve for OS.
图 2 描述了总生存期 (OS) 的卡普兰-迈耶曲线。
Figure 2:& Kaplan-Meier Curve for Overall Survival:& 100 mg Cohort
In a series of exploratory univariate analyses of survival by pretreatment characteristics, including ECOG PS, disease status, gender, age, and EGFR status, all of the HR\"s in the Tarceva and gemcitabine group relative to the placebo plus gemcitabine group were ≤ 1.0.& However, the benefits of Tarceva were uncertain in patients with locally advanced disease, pain intensity scores &20, females, age ≥65 years, or PS 0-1. (Figure 3)
一系列的预处理特征（包括 ECOG PS、疾病状态、性别、年龄和 EGFR 状态）构成的单变量分析中，特罗凯联合吉他西滨组和安慰剂加吉西他滨组中所有危害比 (HR) 都 ≤ 1.0。然而，某些患者接受特罗凯治疗的益处尚不确定，如局部晚期疾病患者、疼痛强度评分&20、女性、年龄 ≥65 岁或体能状态评分 (PS) 为 0-1 的患者。（图 3）
Figure 3:& Survival in Subgroups by Pretreatment Characteristics:& 100 mg Cohort2
Note: Depicted are the univariate HR for death in the patients receiving Tarceva plus gemcitabine relative to the patients receiving placebo plus gemcitabine, the 95% confidence interval (CI) for the HR, and the sample size (N) in each subgroup. The hash mark on the horizontal bar represents the HR, and the length of the horizontal bar represents the 95% confidence interval. A hash mark to the left of the vertical line corresponds to a HR that is less than 1.00, which indicates that survival is better in the Tarceva arm compared with the placebo arm in that subgroup.& Only chemotherapy given concurrently with radiation treatment as a radiosensitizer was allowed.
EGFR Protein Expression StatusEGFR 蛋白质表达状态
In the pivotal pancreatic cancer study, EGFR protein expression status was known in only 26% of patients.2& EGFR expression was determined using the EGFR pharmDx™ kit (Note:& the pharmDx kit has not been validated for use in pancreatic cancer).& A positive EGFR expression status was defined as ≥10% of cells staining positive for EGFR.& Overall, no significant differences were noted in patient or disease characteristics in those with known vs. unknown EGFR status.
在关键的胰腺癌研究中， EGFR 蛋白质表达状态已知的患者仅占 26%。利用 EGFR pharmDx™ 试剂盒（注释：pharmDx试剂盒尚未确认用于胰腺癌）确定 EGFR 表达。阳性 EGFR 表达状态定义为 EGFR 的染色阳性细胞的 ≥10%。总的来说，EGFR 已知和未知的患者或疾病特征中没有注意到显著的差异。
Across all EGFR subgroups (EGFR-positive, EGFR-negative and EGFR-unmeasured), Tarceva plus gemcitabin however, these results did not reach statistical significance.& The survival HRs for EGFR-positive patients was similar to those observed in EGFR-negative patients (0.82 and 0.75, respectively).& These results should be interpreted with caution due to the small sample size.(Figure 4).
所有 EGFR 分组中（EGFR 阳性，EGFR 阴性和 EGFR 未测定的），特罗凯联合吉西他滨延长了存活期；但是，这些结果并没有达到统计学意义。EGFR 阳性患者的存活期危害比与EGFR 阴性患者的存活期危害比相近（分别为 0.82 和 0.75）。由于样本规模小，因此需谨慎解释这些结果。
Figure 4:& Survival in EGFR Positive and Negative Patients Treated with Tarceva (100 mg) and Gemcitabine
&&&&&&&&& EGFR Positive (N=70)
&&&&&&&&& EGFR Negative (N=66)
Progression-Free Survival无进展生存期
The combination of Tarceva and gemcitabine resulted in a statistically significant improvement in PFS.2& The median PFS in the Tarceva and the placebo arms were 3.8 and 3.5 months, respectively (p=0.006).& The adjusted HR was 0.76 (P=0.006) indicating a 24% reduction in the risk of death or disease progression as compared to patients in the placebo plus gemcitabine arm of the study.&
特罗凯联合吉西他滨治疗使得无进展生存期 (PFS) 从统计学的角度看有了显著地提高。特罗凯组和安慰剂组中中位无进展生存期 (PFS) 分别为 3.8 和 ３.5 个月 (p=0.006). 经调节的危害比 (HR) 为 0.76 (P=0.006)，与接受安慰剂加吉西他滨治疗的患者相比，危害比或疾病进展降低了 24%。
Response Rate反应率
Objective responses were observed in 8.6% and 7.9% of patients in the Tarceva plus gemcitabine and placebo plus gemcitabine groups, respectively (p=0.87).& Responses were durable in those patients wit the median response duration was approximately 23 weeks in both treatment arms.& Tumor responses were observed in all EGFR subgroups:& 5.0% in the EGFR-positive subgroup, 9.7% in the EGFR-negative subgroup and 9.2% in the EGFR-unmeasured subgroup.& Stable disease was observed in 50.4% of patients in the Tarceva 100 mg group and in 41.5% of patients in the placebo group (p=0.036).4
观察到接受特罗凯加吉西他滨以及安慰剂加吉西他滨的患者的客观反应分别为 8.6% 和 7.9% (p=0.87)。可测量的疾病的患者中反应是持久的；两组治疗组中，中位反应持续时间约为 23 周。在所有 EGFR 分组中观察到肿瘤缓解: EGFR 阳性分组中为 5.0%，EGFR 阴性分组中为 9.7% 和 EGFR 未测定的分组中为 9.2%。特罗凯（剂量 100 mg）组中疾病稳定的患者占 50.4%，而安慰剂组中占 41.5% (p=0.036)。4
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给陈建清医生的留言列表
&&&&ashzcgd8&& 00:00
化疗的效果
左支气管腺样囊性癌
左支气管有一肿瘤，现在已经手术。左肺切除，但气管残端（0.8cm)病检结果还有癌细胞。现在做放疗，病人现在情况良好。10月23号做的手术，放疗也快结束了，请问这种情况需要化疗吗？化疗的作用大还是副作用大。谢谢。
近期一直没有检查，放疗25次了。前20次是纵膈放疗，后面有15次是对残端放疗。在放疗期间病人情况很好，手术前检查都正常。想问一下您的意见。期待您的回复
淋巴结均未见异常，免疫组化染色显示肿瘤细胞：HER-1(弱+）,HER-2（+）,Calponin(+)，Ki-67(+5%)，P63(+)，Top-lla(+<2%),Ck(+),actin(-).(.....)lla(+<2%),Ck(+),actin(-).
医生回复：&&&&&&&& 00:00
片子现在在北京，无法传送，对您这种认真负责的态度，我表示衷心的谢意。依您的工作经验您给一个建议吧。片子据北京的大夫说很好。谢了。
&&&&vickylyw2d&& 00:00
胃部间质瘤
间质瘤长在胃中间，肿瘤切除，良性
请问在饮食上应注意什么？间质瘤手术怎样才能达到最好效果。
医生回复：&&&&&&&& 00:00
你好：&& 因为资料不详，不好判，尤其手术及病理报告情况，包括间质瘤免疫组化情况ＣＤ117,ＣＤ119情况，还有细胞核分裂情况，是否为高危间质瘤。若为良性则不需其他治疗，临床观察即可。饮食主要是胃手术后变小，功能下降，少吃多餐，定期复查。
&&&&by10-03-31 00:00
卵巢癌低分化腺癌IIIc期，化疗一次，何时添加中医治疗
卵巢癌低分化腺癌IIIc期、脑梗塞、肾炎
患者，66岁，蛋白尿30年，脑梗塞4个月，一月前发现双侧卵巢肿瘤，
4月8日在浙一妇科已手术治疗，手术顺利，4月19日进行第一次化疗。
能否找你看病，何时添加中医治疗，能否不带患者就诊。
医生回复：&&&&&&&& 00:00
TC方案化疗（泰素210mg+卡铂300mg),5月9日行第二次化疗，中间可否加中医治疗
&&&&jamingn60&& 00:00
肺癌晚期服用什么药效果好
食道癌手术后肺转移
咳嗽（吐出的痰中有小泡沫无血）、发烧、气短、心率高
六年前得胃癌
请问吃什么药能控制癌细胞生长，来延长生命
食道癌手术后肺转移，肺部做了介入手术
医生回复：&&&&&&&& 00:00
张先生好：&& 从介绍看好像有些矛盾。一会儿是胃癌晚期，又是食管癌术后复发肺转移，有待进一步明确。可能为胃底贲门癌术后复发肺转移，是腺癌吗？那么还是以胃癌为原发灶，治疗应用胃癌方面的治疗。先抗炎为主，可能肺功能很差，发热、气短，不宜化疗，最好住院抗炎。以对症治疗为主，有条件可以考虑替吉奥口服化疗控制肿瘤生长，副作用小，可以耐受。&& 以上仅供参考。
&&&&pingan131d6&& 00:00
我母亲做了结肠癌切除手术，出院一年来身体不错，可近来出现腹胀，呕吐，肛门下坠，不知是否发生了癌转移？
我母亲，去年做了结肠癌切除手术，出院近一年来身体不错，可近来出现腹胀，呕吐，肛门下坠，不知是否发生了癌转移？
已切除并经过化疗，效果较好。
想知道是否发生了癌转移？
医生回复：&&&&&&&& 00:00
你好：&& 首先明确结肠癌分期如何？还有手术情况。发生呕吐可能性：1、术后肠梗阻，系粘连所致；2、术后复发，为肿瘤侵犯肠道或腹腔种植引起。需进一步检查，可以行腹部立位平片、盆腔CT以及PET——CT检查，有些可能还需腹腔镜检查才能明确。
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