我父亲肺鳞癌的治疗贴(2014年3月1日驾鹤西去）

老马 · 发表于 2012-8-5 20:07:28

her2基因在肺癌中的研究进展.pdf (292.5 KB, 下载次数: 98)

老马 · 发表于 2012-8-5 20:09:12

HER2/neu(erbB2)基因，编码蛋白大小为185KDa，具有酪氨酸蛋白激酶活性，为表皮生长因子受体(EGFR)家族成员，与EGFR高度同源。HER2/neu蛋白可以与家族其他成员形成异源二聚体，从而发挥强有力的肿瘤信号传导作用。研究显示，HER2/neu介导的信号传导与肿瘤的形成、增殖、转移、侵袭及放化疗耐受有关。约1/3非小细胞肺癌(NSCLC)存在HER2/neu过表达，其在NSCLC形成、增殖、转移、侵袭等方面的作用尚需进一步研究证实。

老马 · 发表于 2012-8-6 00:38:22

Clin Lung Cancer. 2004 Jan;5(4):231-6.

Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial.

Lara PN Jr, Laptalo L, Longmate J, Lau DH, Gandour-Edwards R, Gumerlock PH, Doroshow JH, Gandara DR; California Cancer Consortium.

Source

Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, Sacramento, CA 95817, USA. primo.lara@ucdmc.ucdavis.edu

Abstract

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.

老马 · 发表于 2012-8-6 00:42:19

Cancer. 2005 Apr 15;103(8):1670-5.

Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B.

Clamon G, Herndon J, Kern J, Govindan R, Garst J, Watson D, Green M; Cancer and Leukemia Group B.

Source

Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242-1099, USA. gerald-clamon@uiowa.edu

Abstract

BACKGROUND:

The overexpression of HER-2 occurs in a minority of patients with nonsmall cell lung carcinoma. Trastuzumab, which is a monoclonal antibody to HER-2, is an effective treatment in some women with breast carcinomas that overexpress HER-2, as demonstrated by immunohistochemistry. The objective of this Phase II study was to determine whether trastuzumab would effect responses in patients with nonsmall cell lung carcinoma who had tumors that overexpressed HER-2.

METHODS:

Patients were required to have Stage IIIB or Stage IV nonsmall cell lung carcinoma and tumors with 2+ or 3+ expression of HER-2, as determined with immunohistochemistry, and they may have received up to 1 prior chemotherapy regimen. Trastuzumab at a dose of 4 mg/kg was given intravenously on Week 1; then, weekly doses of 2 mg/kg were given. Response revaluation was performed every 8 weeks.

RESULTS:

Among 209 screened patients, 24 patients (11%) had tumors with 2+ or 3+ expression of HER-2. One patient achieved a partial response, and one patient experienced a treatment-related death due to pulmonary toxicity.

CONCLUSIONS:

Single-agent trastuzumab did not exhibit significant clinical activity against nonsmall cell lung carcinoma when HER-2 expression levels were measured by immunohistochemistry.

老马 · 发表于 2012-8-6 00:52:47

J Clin Oncol. 2004 Apr 1;22(7):1180-7. Epub 2004 Feb 23.

Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598.

Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH; Eastern Cooperative Oncology Group Study 2598.

Source

Fox Chase Cancer Center, Philadelphia, PA 19111, USA. CJ_Langer@fccc.edu

Abstract

PURPOSE:

Multiple non-small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC.

MATERIALS AND METHODS:

Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction >or= 45%. Patients received paclitaxel 225 mg/m(2)/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for <or= 1 year.

RESULTS:

Between August 1999 and May 2000, 139 patients were screened; seven specimens (5%) were indeterminate. Fifty patients (36%) were HER-2/neu negative, 38 (27%) were HER-2/neu 1+, 31 (22%) were 2+, and 13 (9%) were 3+. Fifty-six patients were enrolled; 53 were eligible (22 [42%] were 1+, 23 (43%) were 2+, and eight (15%) were 3+). Thirteen (24.5%) of 52 assessable patients (95% CI, 13.8 to 38.3) responded. The incidence of grade >or= 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade <or= 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%.

CONCLUSION:

Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumab's role in advanced NSCLC will require phase III trials.

老马 · 发表于 2012-8-6 01:10:51

本帖最后由老马于 2012-8-6 01:14 编辑

http://cancergrace.org/lung/topi ... s-metastatic-nsclc/
Diagnosed & lobectomy in summer 2005 (BAC and mixed adenocarcinoma)
4 cycles of cisplatin/vinorelbine fall 2005-jan 2006; recurrence by feb. 2006
Tarceva april 2006; diagnosed as incurable July 2006
Avastin added to Tarceva August 2006 to Feb. 2007; progression of disease
Alimta and Avastin winter 2007–january 2009; slow progression in lungs but metastasis to spine
July 2009 resection of L2 spinal tumor, plus radiation
November 2009 Gemcitabine; progression
May 2010 tests negative for ALK (already knew neg. for EGFR/KRS)
July 2010 begins clinical trial Afatinib: regression of 15%
by August 2011 new lesion in tailbone area/T11; progression and spinal lesions T11, T12, L2 and coccyx by Feb. 2012
Vertebroplasty/radiofrequency ablation of T11 Feb. 2012, requiring exclusion from trial
Feb. 2012 tests positive for HEr2 mutation

DR.west:
Though there is really no way to know, I agree that it’s a good thought that the afatinib (BIBW2992) benefit may be more due to HER2 than to EGFR.

As for whether to pursue typical treatments for HER2 along the lines of breast cancer, this is really an untested question. Still, I do agree that it’s tempting to consider a chemo/Herceptin (trastuzumab) combination, which is all but unstudied in lung cancer, but it’s not a huge leap to think it could be quite beneficial. Another agent that is commercially available against the HER2 target is an oral agent called Tykerb (lapatinib) that also acts against EGFR and HER2, so pretty similar to afatinib, but possibly helpful.

Dr West:
The main treatments that were discussed, all very briefly, were afatinib, ARRY 380, dacomitinib, AZD 8931, HER2 doxorubicin, and MM 111. I’m sorry I can’t feasibly cover them all here, but if you want to do a search for trials, they all target HER2, in some cases in combination with other members of the HER family.

老马 · 发表于 2012-8-6 01:17:29

2012年第三届欧洲肺癌大会侧记
议题1 Panel Discussion：NCSCL的维持治疗

主要流程是先通过投票形式询问医生对维持治疗的观念，然后有正反两方分别阐述自己的观点，再由医生回答之前提出的问题，最后自由讨论。通过选票形式询问医生对维持治疗的观点。

1.多数医生(66.9%)支持一线应用化疗需要4～6个周期。
   2.当化疗2个周期后发现患者EGFR突变，多数医生(56.5%)认为再接着用2个周期化疗，然后用TKI维持治疗。
   3.多数医生(50.6%)决定是否要维持治疗要看患者对化疗的反应情况。
   4.吸烟的肺腺癌患者应用化疗4个周期后部分缓解，下一步如何处理：多数医生(48.1%)选择观察，另一部分医生(33.7%)选择应用培美曲塞维持。
   5.吸烟的肺腺癌患者如果一开始就用的培美曲塞，下一步如何处理：多数医生(55.6%)选择继续用培美曲塞，一部分医生(33.6%)选择观察。
   6.吸烟的肺鳞癌患者应用化疗4个周期后PR，下一步如何处理：多数医生(71.3%)选择观察。

正方：Giorgio医生  支持维持治疗

1. 30%～40%的患者进入不了二线治疗。
   2. 如果肿瘤治疗的目的是让肿瘤成为慢性病，那么就需要慢性治疗。
   3. 维持治疗可以延长患者达到疾病进展的时间，使患者生活质量更好，生存时间更长。
   4. 疾病进展产生的后果较维持治疗的不良反应严重。
   5. 什么药物更适合维持治疗：EGFR突变的患者应用厄洛替尼；EGFR阴性的肺腺癌患者用培美曲塞。

反方：Shepherd医生  不支持维持治疗

1. 维持治疗的很多数据还不完整。
   2. 维持治疗延长无进展生存时段有限，基本只有1个月，相比而言，总生存(OS)时间改善基本没有差异。
   3. 毒性反应高于非维持治疗，恶心、呕吐等不良反应导致生活质量下降。
   4. 费用高，经济负担重。

再次投票表决结果

1. 支持一线应用化疗需要4～6个周期的人数上升(71.4%：66.9%)。
   2. 多数医生(50.6%)决定是否要维持治疗要依患者对化疗的反应情况而定。
   3. 当化疗2个周期后发现患者EGFR突变，支持继续维持2个周期化疗，然后用TKI治疗的人数增加(65.5%：56.5%)。
   4. 吸烟的肺腺癌患者应用化疗4个周期后PR，下一步如何处理：选择观察的医生人数明显上升(72.6%：48.1%)，选择应用培美曲塞维持的人数明显下降(18.3%：33.7%)。
   5. 吸烟的肺腺癌患者如果一开始就用的培美曲塞，下一步如何处理：选择观察的医生人数明显上升(48.3%：33.6%)，选择继续用培美曲塞维持治疗的人数下降(46.5%：55.6%)。
   6. 吸烟的肺鳞癌患者应用化疗4个周期后PR，下一步如何处理：选择观察的医生人数上升(84.8%：71.3%)。

●评论

经过正反方证据的阐述，支持维持治疗的医生人数下降；如果给予维持治疗，多数医生建议：EGFR突变的患者应用厄洛替尼；EGFR阴性的腺癌患者使用化疗培美曲塞。

老马 · 发表于 2012-8-6 01:18:09

议题1 新的TKI药物：Docomitinib

研究1：来自英国F.Blackhall医生

英国F.Blackhall医生报告了Dacomitinib(PF-00299804) 在难治性非腺癌NSCLC中的疗效及二、三线治疗与厄洛替尼的对比研究。

Dacomitinib是作用于HER-1/EGFR、HER-2及HER-4不可逆的TK抑制剂；两项Ⅱ期研究评价了Dacomitinib单药：用于1个以上的化疗方案及厄洛替尼治疗失败的KRAS野生型NSCLC患者；1个或2个化疗方案失败的晚期NSCLC患者；2项研究均包括非肺腺癌患者。

该研究得出的结论认为，BR.21研究结果厄洛替尼与安慰剂对比二线或三线治疗NSCLC，中位无进展生存及OS分别为2.2个月和6.7个月；Dacomitinib治疗化疗或厄洛替尼耐药非腺癌的中位无进展生存期及总生存期分别为11.1周(2.6 个月)、26.2周(6.1个月)；Dacomitinib与厄洛替尼治疗二线或三线治疗NSCLC非腺癌的中位无进展生存期相似(8.7周 vs. 8.0周)，然而生存曲线分离；D要高于E(HR为0.64)，有35%的改善；

Dacomitinib作用于不同组织类型的Ⅲ期研究中正在进行的有BR.26研究：Dacomitinib与安慰剂治疗耐药的NSCLC；ARCHER 1009研究：Dacomitinib与厄洛替尼对比。

研究2：来自瑞士Pfizer AG教授

瑞士Pfizer AG教授报告了Dacomitinib与厄洛替尼治疗化疗失败的进展期NSCLC患者 Ⅱ期的随机临床试验。
该试验的研究结果显示Dacomitinib与厄洛替尼相比可以延长无进展生存期；Dacomitini主要控制NSCLC患者的临床症状，提高了生活质量。

此研究结果为以后的HRQoL试验提供强有力的理论依据：全球的Ⅲ期临床研究ARCHER 1009以及最近Dacomitinib与厄洛替尼比较二线或三线治疗NSCLC的疗效评价等研究均应用这些指标。

老马 · 发表于 2012-8-6 01:24:54

6. 中国人NSCLC患者驱动基因在的变化状态

我国吴一龙教授报道了中国人NSCLC患者驱动基因在的变化状态，在吸烟和不同病理类型的富集基因是不一样的。将受试者分为不吸烟的腺癌、吸烟的腺癌、不吸烟的鳞癌及吸烟的鳞癌4组，分析后显示，4组NSCLC患者的EGVFR突变率分别为49.8%、22%、8%和2.1%；ALK突变率分别为9.3%、4.5%、0和6.5%，KRAS突变在吸烟的腺癌组最高(12%)，PENT阳性在吸烟的鳞癌组最高(16.1%)，其他基因相对变化较小，对我们今后的临床研究是很有帮助的，提供了基础研究的依据。