“NSCLC分子诊断测试的变化趋势需要定期更新现有指南”在非小细胞肺癌分子诊断测试的变化现状需要定期更新现有的分子测试指南。美国病理学家学会、国际肺癌研究协会和分子病理学协会已经发布了一份最新的分子检测指南,用于选择肺癌患者进行靶向治疗。更新后的指南规定,细胞学准备要保证进行分子检测的足够样本,建议不要使用免疫组织化学(IHC)来测定EGFR的表达,以指导使用EGFR-TKIs,并将基于IHC的ALK检测作为荧光原位杂交(FISH)的替代方法,除了基于IHC的ROS1筛查。该指南还建议对晚期肺腺癌患者进行单独的ROS1检测,将其他基因(RET、HER2、KRAS、BRAF和MET)作为更大测序面板的一部分纳入,并在一线EGFR-TKIs进行进展后检测EGFRT790M。建议进行分子生物标志物检测的临床病理学特征描述,如有无烟草暴露和是否年轻(定义为<50岁),并为临床提供建议cfDNA的应用。ASCO对该指南进行了一些小的修改,主要包括在晚期腺癌患者中使用独立的BRAF测试。基因组学驱动的癌症治疗范围的扩大,将由最新指南的广泛采用推动,在许多层面上具有一系列实际意义。首先,考虑到需要评估越来越多的分子标记来指导治疗选择的有效性,获得高质量的肿瘤组织样本并有效利用这些肿瘤样本将是当务之急。第二,虽然早期的证据表明RET、HER2和MET中的突变可能都是相关的治疗靶点,而且非标签使用商业认可的靶点治疗是一种潜在的治疗选择,应尽可能考虑临床试验注册,以充分阐明这些基因组改变的临床重要性,并确定最佳治疗策略。目前为止,直接靶向突变型KRAS一直是一个挑战,尽管正在进行试验,以检验间接靶向KRAS的新组合的疗效。第三,了解现有的分子诊断的效用和局限性对于患者治疗至关重要。尽管cfDNA具有高度的特异性,但对存在EGFRT790M突变的cfDNA的分析仅具有中等水平的敏感性,因此,如果血浆cfDNA分析结果为阴性,则应考虑对组织样本的评估。当IHC对ALK的检测结果不确定时,应用FISH或分子检测(如下一代测序(NGS)或逆转录(RT-PCR))指导治疗。对于ROS1检测,阳性IHC结果应使用FISH或DNA测序方法进行确认。第四,NGS现在可以被用于检测易位和拷贝数的变化,以及突变,具有很高的准确性。后续减少成本可能使得在研究和临床环境中更广泛地采用全面的NGS技术(如全外显子组测序),从而产生大量的测序数据。有了如此大量的数据,最艰巨的任务之一就是将数据转换为治疗决策。为了应对这一挑战,需要与所有利益相关者建立合作伙伴关系,开发大型数据库,将基因组数据与临床结果联系起来,并在基因组生物标记物驱动的临床试验的设计和实施方面实现创新。
一、哪类患者属于局部晚期肺癌一般而言III期肺癌被认为属于局部晚期肺癌。对于这部分患者存在较大的异质性。目前而言,对于这类患者可以分为两类:可手术和非手术患者,一般而言对于纵隔多发淋巴结转移的N2患者不提倡直接手术,而对于N3患者则视为非手术治疗范畴。二、非手术治疗的手段的基石放化疗目前III期患者的非手术治疗主要是放疗+化疗的治疗,目前的循证依据表明同步放化疗相比于序贯化疗后放料的模式,能提高患者总生存。并且在同步放化疗之前或之后加用化疗并没有明显提高疗效。同步化疗的药物最经典的方案仍然是NP为主。采用同步放化疗的决策需要充分考虑患者的耐受性。三、免疫治疗在局部晚期肺癌中的治疗虽然同步放化疗是标准治疗方案,但疗效依然有待提高。目前理论支持放化疗后可能产生肿瘤相关抗原,但由于肿瘤存在免疫逃逸机制抑制了T细胞的杀伤肿瘤细胞,而目前PD-1,PD-L1抑制剂如图可以抑制肿瘤的逃逸机制。2017年新英格兰医学杂志发表Pacific的III期临床研究,同步放化疗后继续使用Durvalumab,使用该药后患者中位PFS达到16.8月,比安慰剂组5.6月明显延长。有趣的是在治疗之前的PD-L1的表达即使弱阳性依然是有效的。亚组分析显示放疗后越早进行免疫治疗的疗效更好。2018年LUN14-179研究也同样显示了Pembro药物在同步放化疗后继续使用也能获得类似PFS结果。本文系赵胜光医生授权好大夫在线(www.haodf.com)发布,未经授权请勿转载。
胰腺导管内乳头状粘液瘤(IPMN)的发病率随诊断技术的发展正在逐年上升,目前占胰腺囊性病变的30%左右。IPMN的特点是具有潜在恶变的特点,还没有恶变的IPMN的10年疾病相关生存率超过95%,一旦IPMN含有侵袭性癌变5年总生存率不到前者的一半。 总的来说,IPMN癌变后的预后要好于常见的胰腺侵润性导管腺癌。麻省总院报道导管内乳头状粘液癌的淋巴结转移概率大约为30%,与典型的胰腺癌侵润性导管癌70%左右的淋巴结转移概率而言明显不同。而且大多肿瘤病理分期为II期,不同于侵润性导管癌大多都是晚期为主。 IPMN的病理分型为肠型, 胰腺胆管型,嗜酸细胞型,胃型等等,主要以肠型为主。 一般而言,IPMN从良性到恶变的过程目前仍然尚不明确。但一般认为整过程至少需要经历5-7年。其中以主胰管的恶变概率高于分支胰管,其发生概率超过50%。 从预后而言,主要根据手术病理,肿瘤分化程度,淋巴结转移,血管侵犯,手术未能完全切除,等等均是判断预后的主要依据。流行病学研究发现,淋巴结转移的IPMN5年总生存仅12%,远远低于没有发生淋巴结转移的IPMN。 治疗的主要手段是手术,根据2012年欧美胰腺癌多学科专家组的意见,主胰管IPMN无论位于胰头还是胰尾,也无论肿瘤大小均建议手术。要求手术切缘尽可能达到阴性。而对于分支胰管则需要根据囊性病变的直径大小,囊壁的厚度,与主胰管的关系,以及细胞穿刺学来具体分析是否需要手术。 手术的后续治疗目前仍在探索中,目前按照胰腺癌的管理原则对于IPMN也并不是完全适合。良性IPMN一般无需进一步治疗,而有侵润性的IPMN,根据现有的资料显示,对于肿瘤无法彻底完全切除的IPMN,或者手术中发现有淋巴结侵犯的IPMN,均建议行放化疗为主的治疗。
一般来说,Ca 199作为肿瘤血清学指标,尤其在胰腺癌方面的诊断价值较高。但是在平时的工作中经常会有一些CA199异常增高的人群,就以下分析:1.如果体检发现Ca 199轻度增高,主要考虑是否有胆管胰腺炎性改变,需要在完成胰腺检查后定期随访。2.如果Ca 199 持续增高或者超过100以上需要警惕恶性肿瘤的可能性,重点查胰腺CT,必要时候需要全身检查3.如果原来就患有肿瘤的患者,无论是胰腺癌患者还是其他肿瘤,均要警惕是否有复发转移迹象4.单一Ca 199需要联合其他肿瘤指标以及影像学资料综合判断
摘要 目的 分析移动式直线加速器Mobetron实施术中放疗(IORT)中的潜在风险,初步探讨优化IORT各步骤的管理、减少潜在风险发生的可行性。方法 由IORT团队(2名外科医生、2名放疗科医生、1名放疗物理师、1名放疗技术员、2名护士)应用失效模式和效果分析(FMEA)开展系统风险评估。确立流程模块,对每项模块分析潜在失效模式,对失效模式行频度(OR)、严重度(SR)、探测度(DR)评分,计算风险优先指数(RPN)。结果 IORT流程分为9个模块,15项失效模式。OR最高值为激光软对位时间明显延长(8分),SR最高为Mobetron设备故障无法出束(10分),DR最高值为是剂量计算中发生的数据查询误差(8分),RPN最高为靶区确认不满意(198分)和未有效保护正常组织(180分)。对每项失效模式均行原因和现行措施分析并提出预防措施。结论 FMEA是一种有效的IORT管理方法,有助于减少潜在风险发生。
摘要:目的 用CT血管造影(CTA)技术勾画冠状动脉左前降支(LAD)并分析其空间走向,初步探讨各种左侧乳腺癌术后放疗技术对LAD的影响.方法 对29例平均年龄54.71岁乳腺癌治疗后复查女性行CTA并勾画LAD,同时在T7~ T8、T8~ T9、T9~ T10胸椎间隙水平,乳头、乳腺下缘水平测量LAD至胸壁(前后向)、左内乳动脉(水平向)、室间沟(斜向)距离,分析其空间走向.取2例左侧乳腺切除术后患者(LAD起始部位分别在T3、T4胸椎间隙水平)和1例左侧保乳术后患者分别采用不同切线野、内乳野放疗技术照射并分析LAD受照情况.结果 29例患者LAD起始部位于第3肋间隙(40%)或第4肋间隙水平(60%),长度为(7.49±0.58) cm.T7~ T8、T8~ T9、T9~ T10水平LAD至前后方向距离分别为(2.99±1.11)、(1.26±0.65)、(0.68±0.39) cm,至水平方向距离分别为(2.27±0.84)、(2.81±0.65)、(3.37±1.21) cm,至斜方向距离分别为(0.47±0.25)、(0.38±0.21)、(0.42±0.19) cm;乳头、乳腺下缘水平LAD至前后方向距离分别为(2.94±1.06)、(0.79±0.46) cm,至水平方向距离分别为(2.45±0.89)、(3.32±1.22) cm,至斜方向距离分别为(0.56±0.30)、(0.57±0.24) cm.结论 勾画LAD可以将室间沟作为主要参考点,切线野照射技术可能对LAD的剂量影响较高。
Hypopharyngeal Dose Is Associated With Severe Late Toxicity in Locally Advanced Head-and-Neck Cancer: An RTOG Analysis15 November 2012Mitchell Machtay | Jennifer Moughan | Andrew Farach | Elizabeth Martin-O'Meara | James Galvin | Adam S. Garden | Randal S. Weber | Jay S. Cooper | Arlene Forastiere | K. Kian AngPurposeConcurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity.Methods and MaterialsThis was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube ≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors.ResultsA total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P=.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P=.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome.ConclusionsSevere late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.头颈部放疗勾画靶区和正常组织最能体现一名放疗医生的勾画能力,勾画能力越强,勾画组织越多,评估就越完善,患者获益就越多。
AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells15 November 2012Pavithra Raghavan | Vasu Tumati | Lan Yu | Norman Chan | Nozomi Tomimatsu | Sandeep Burma | Robert G. Bristow | Debabrata SahaPurposeRadiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT.Methods and MaterialsThe combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used.ResultsTreatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G2-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7.ConclusionsThis study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.
Five-year Results of Whole Breast Intensity Modulated Radiation Therapy for the Treatment of Early Stage Breast Cancer: The Fox Chase Cancer Center Experience15 November 2012Lanea M.M. Keller | Dennis M. Sopka | Tianyu Li | Tracy Klayton | Jinsheng Li | Penny R. Anderson | Richard J. Bleicher | Elin R. Sigurdson | Gary M. FreedmanPurposeTo report the 5-year outcomes using whole-breast intensity-modulated radiation therapy (IMRT) for the treatment of early-stage-breast cancer at the Fox Chase Cancer Center.Methods and MaterialsA total of 946 women with early-stage breast cancer (stage 0, I, or II) were treated with IMRT after surgery with or without systemic therapy from 2003-2010. Whole-breast radiation was delivered via an IMRT technique with a median whole-breast radiation dose of 46 Gy and median tumor bed boost of 14 Gy. Endpoints included local-regional recurrence, cosmesis, and late complications.ResultsWith a median follow-up of 31 months (range, 1-97 months), there were 12 ipsilateral breast tumor recurrences (IBTR) and one locoregional recurrence. The 5-year actuarial IBTR and locoregional recurrence rates were 2.0% and 2.4%. Physician-reported cosmestic outcomes were available for 645 patients: 63% were considered “excellent”, 33% “good”, and <1.5% “fair/poor”. For physician-reported cosmesis, boost doses ≥16 Gy, breast size >900 cc, or boost volumes >34 cc were significantly associated with a “fair/poor” cosmetic outcome. Fibrosis, edema, erythema, and telangectasia were also associated with “fair/poor” physician-reported cosmesis; erythema and telangectasia remained significant on multivariate analysis. Patient-reported cosmesis was available for 548 patients, and 33%, 50%, and 17% of patients reported “excellent”, “good”, and “fair/poor” cosmesis, respectively. The use of a boost and increased boost volume: breast volume ratio were significantly associated with “fair/poor” outcomes. No parameter for patient-reported cosmesis was significant on multivariate analysis. The chances of experiencing a treatment related effect was significantly associated with a boost dose ≥16 Gy, receipt of chemotherapy and endocrine therapy, large breast size, and electron boost energy.ConclusionsWhole-breast IMRT is associated with very low rates of local recurrence at 5 years, 83%-98% “good/excellent” cosmetic outcomes, and minimal chronic toxicity, including late fibrosis.看看国外用了那么久的好技术,国内应用的医院屈指可数,大多医院还是倾向与三维适行放疗,不是说老技术不好,但是科学的进步是需要不断学习的。
The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical PerspectiveSummary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the clinicaltrials.gov Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with clinicaltrials.gov protocols.We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies.In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such trials are not given priority by pharmaceutical companies. The potential reasons for this and some challenges and possible solutions are discussed.靶向和放疗在头颈部已经定论,肺癌那么多的靶向药物希望能有更多的临床结果报道