非小细胞肺癌（NSCLC）的化疗宝典

Continuous pemetrexed treatment for brain metastasis in non-small cell lung cancer-A report of two cases.
Nobuaki Ochi, Hiromichi Yamane, Tomoko Yamagishi, Nagio Takigawa
Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.
Lung cancer (Amsterdam, Netherlands) (Impact Factor: 3.14). 12/2012; DOI:10.1016/j.lungcan.2012.12.010
Source: PubMed
ABSTRACT Brain metastasis is a major complication in patients with advanced non-small cell lung cancer (NSCLC), which is the malignancy that metastasizes most frequently to the central nervous system (CNS). Although the CNS is protected from cytotoxic agents by the blood-brain barrier under normal conditions, the blood-brain barrier is thought to become less functional in the presence of brain metastasis. Here, we describe two NSCLC patients who relapsed with brain metastases. Following brain stereotactic irradiation, salvage chemotherapy using pemetrexed was given. Continuous pemetrexed treatment resulted in no recurrence, including brain metastasis, over 2 years without whole-brain irradiation. Our experience suggests that pemetrexed suppresses brain metastasis after stereotactic irradiation.

http://www.researchgate.net/publ ... report_of_two_cases

Maintenance Therapy for Advanced Lung Cancer: Who, What, and When?
http://jco.ascopubs.org/content/31/24/2983

Efficacy assessment of pemetrexed treatment of an NSCLC case with brain metastasis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499519/
Efficacy assessment of pemetrexed treatment of an NSCLC case with brain metastasis.PDF (425.45 KB, 下载次数: 598)

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Case Study: Maintenance Therapy in Squamous NSCLC
http://www.onclive.com/peer-exch ... y-in-Squamous-NSCLC
In the continuation of a case-based discussion, panelists describe the appropriateness of maintenance therapy for a functional 77 year-old man with squamous non-small cell lung cancer (NSCLC). The patient should receive an initial doublet therapy, administered on a weekly schedule, suggests Everett E. Vokes, MD. Following 4 to 6 weeks of treatment, maintenance therapy should be discussed as an option but should not automatically be administered, Vokes believes.

Erlotinib was suggested as a potential maintenance therapy; however, Karen L. Reckamp, MD, MS, notes that she does not utilize it in this setting. If a patient responds well to the initial regimen, such as gemcitabine, without significant toxicity, Reckamp suggests continuing this treatment. However, if the initial regimen includes a taxane, a break from treatment may be required.

While he would not automatically recommend maintenance therapy, Roy S. Herbst, MD, PhD, does discuss it as an option with his patients. If maintenance is required, Herbst recommends erlotinib or gemcitabine. Following the initial treatment, the patient should be observed for signs of continued tumor growth by imaging every 8 weeks to 3 months.

At this point, moderator Corey J. Langer, MD, changes the scenario by noting that the patient has adenocarcinoma rather than squamous cell NSCLC. Outside of this, the clinical presentation is the same. In this situation, Langer wonders if treatment with bevacizumab is appropriate. This patient should still be treated with an initial doublet regimen and not a single agent, Vokes emphasizes. Additionally, he adds, given the patient's age, there is not an advantage for adding bevacizumab to the doublet.

Case Study: Treating an Elderly Patient With Squamous NSCLC
http://www.onclive.com/peer-exch ... With-Squamous-NSCLC
In the first installment of the series, moderator Corey J. Langer, MD, introduces the panelists for an in-depth discussion on current and emerging treatments for patients with non-small cell lung cancer (NSCLC). The panelists include: Roy S. Herbst, MD, PhD, Karen L. Reckamp, MD, MS, Anne S. Tsao, MD, and Everett E. Vokes, MD.

To begin the discussion, Langer describes a scenario detailing the diagnosis of a functional 77 year-old man with squamous cell NSCLC. The patient presented with right upper quadrant pain and a cough. The initial chest x-ray showed a right upper lobe mass. As a result, a CT scan was administered and found a 4 cm spiculated lesion and hepatic metastases. Additionally, a physical examination by the patient's primary care physician found an enlarged right supraclavicular node and rhonchi at the right base. As a result, the patient underwent a core biopsy that revealed purely squamous cell carcinoma. However, Langer notes, the patient's performance status is intact and he wishes to continue with his daily activities, which include golf.

For elderly patients it is important to look at the performance status (PS), explains Tsao. In this case, the PS is low enough that a platinum-based doublet can be administered safely. In most cases, Tsao utilizes carboplatin with paclitaxel or docetaxel; however, she notes, other regimens have showed efficacy, including platinum-based therapy with gemcitabine or nab-paclitaxel (Abraxane). These alternate regimens offer unique attributes; for instance, Tsao notes, nab-paclitaxel allows for a higher taxane dose with less neuropathy, which is ideal in an elderly population.

There is a clear benefit for treating patients in this setting with a chemotherapy doublet, explains Reckamp. In a phase III trial comparing carboplatin plus paclitaxel to single-agent vinorelbine or gemcitabine the doublet was associated with a significant survival advantage. This trial included patients with PS 0-2, notes Reckamp. While the doublet did result in higher toxicities, the overall outcome was superior. As such, it is important to discuss these factors with the patient before proceeding with a treatment.

Herbst supports a platinum-based doublet; however, focusing on quality of life, the toxicity profile of nab-paclitaxel is promising, specifically since the patient mentioned a desire to continue playing golf.

Case Study: Mutation-Negative Patient With Adenocarcinoma
http://www.onclive.com/peer-exch ... With-Adenocarcinoma
Moderator, Corey J. Langer, MD, begins a case-based discussion on the treatment of a 46 year-old woman with a history of heavy smoking and a diagnosis of non-squamous, non-small cell lung cancer that is negative for mutations in EGFR, ALK, ROS1, and KRAS.

The patient presented after experiencing dyspnea on exertion and right-sided rib pain, explains Langer. A chest x-ray showed a 3 cm left upper lobe mass, suggesting hilar mediastinal adenopathy. Also, Langer notes, there is a clear lytic lesion in the rib. A CT and PET scan confirms these initial findings and shows areas of osseous metastases. However, an MRI of the brain returned negative.

Unfortunately, Roy S. Herbst, MD, PhD, notes, this patient tested negative for all 4 of the major driver mutations. Given the patient's performance status and age, Herbst feels she is a good candidate for a platinum-based therapy with carboplatin plus pemetrexed. Moreover, with the performance status intact, Herbst may add bevacizumab to the combination, per findings from the PointBreak trial.

When considering a combination it is important to consider toxicity, efficacy, and costs, believes Karen L. Reckamp, MD, MS. In the PointBreak trial, the regimen of carboplatin, paclitaxel, and bevacizumab followed by maintenance bevacizumab had similar outcomes to carboplatin, pemetrexed, plus bevacizumab with maintenance pemetrexed and bevacizumab. However, when considering costs, the addition of both pemetrexed and bevacizumab adds an additional $7,000 per cycle and up to $300,000 depending on the length of maintenance therapy.

As a result of the costs and similar efficacy, if utilizing bevacizumab in this space, Reckamp would opt for the carboplatin, paclitaxel, and bevacizumab regimen followed by maintenance bevacizumab. However, if omitting bevacizumab, Reckamp would administer pemetrexed plus carboplatin with single-agent pemetrexed as maintenance.

In the AVAPERL trial, maintenance therapy with bevacizumab plus pemetrexed demonstrated longer progression-free survival when compared to bevacizumab alone, points out Anne S. Tsao, MD. As a result, it remains unclear whether a combination or a single agent for maintenance therapy is superior. To address this concern, the phase III ECOG 5508 trial is comparing maintenance therapy with pemetrexed alone, bevacizumab alone, or pemetrexed plus bevacizumab following 4 cycles of carboplatin, paclitaxel, plus bevacizumab.   

The AVAPERL trial demonstrated similar findings to other maintenance therapy trials, such as JMEN that showed a survival advantage for single agent pemetrexed, suggests Everett E. Vokes, MD. When considering costs, and the similar efficacy of the combinations, Vokes recommends utilizing carboplatin, paclitaxel, and bevacizumab as an initial treatment followed by single-agent pemetrexed as maintenance.

The JMEN trial had limitations, points out Reckamp. However, when also considering the PARAMOUNT trial it remains clear that pemetrexed is an important maintenance drug. In this trial, single agent pemetrexed maintenance prolonged overall survival. At this point, equivalent data is lacking for maintenance bevacizumab, Reckamp notes.

PRONOUNCE Trial: Two Drug Versus Three Drug Regimens
http://www.onclive.com/peer-exch ... Three-Drug-Regimens
The phase III PRONOUNCE study compared a doublet of pemetrexed plus carboplatin followed by maintenance pemetrexed to a triplet of paclitaxel, carboplatin, and bevacizumab with maintenance bevacizumab as a treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). The trial had an unusual primary endpoint that assessed progression-free survival without grade 4 toxicity (G4PFS), explains Corey J. Langer, MD.

The question that the PRONOUNCE trial sought to answer is important, since these regimens are commonly used and demonstrated similar efficacy in separate trials, says Everett E. Vokes, MD. However, the PRONOUNCE trial fell short of answering this question, since a statistically significant difference in survival was not observed. Additionally, Vokes notes, the primary endpoint of G4PFS seemed engineered to favor pemetrexed. Despite the pemetrexed-containing doublet having a numerical advantage for G4PFS, this benefit was not statistically significant.

The primary endpoint of G4PFS has not been validated, notes Anne S. Tsao, MD. As such, it is not typically seen in clinical trials and may have limited utility. Adding to this criticism, Langer remarks that the G4PFS endpoint failed to include neuropathy, taxane-based toxicity, or lower grade events, which are more common. Had this endpoint included these factors, the trial may have been positive, Langer speculates.

Case Study: Second-Line Treatment of Adenocarcinoma
http://www.onclive.com/peer-exch ... t-of-Adenocarcinoma
In a case-based discussion, moderator Corey J. Langer, MD, describes a 46 year-old patient with a diagnosis of non-squamous, non-small cell lung cancer that is negative for mutations in EGFR, ALK, ROS1, and KRAS. The patient received an initial pemetrexed-containing regimen followed by maintenance bevacizumab along with zoledronic acid for 6 months. At this point, the patient progressed with bone metastases.

Docetaxel or erlotinib are potential treatment options in the second-line setting, suggests Roy S. Herbst, MD, PhD. However, utilizing erlotinib in the absence of an EGFR mutation doesn't demonstrate additional benefit, adds Herbst. However, for patients without an EGFR mutation, the VeriStrat test can be used to help predict response based on blood-based proteins.

In the phase III PROSE trial that examined the test, patients categorizes as good had similar survival outcomes when treated with erlotinib and chemotherapy. However, those with a poor status, benefit more from chemotherapy than erlotinib. Proteomic-based classifiers could help determine appropriate treatments; however, the VeriStrat test may still require further validation, Herbst believes. As a result, Herbst suggests utilizing docetaxel as a second-line treatment.

The PROSE trial did not indicate that VeriStrat was a positive predictor for benefit from erlotinib but it did suggests patients who would not benefit, Anne S. Tsao, MD adds. Moreover, many of the prognostic groups identified by the test coincided with other identifiable clinical factors. However, looking at the full picture, Herbst believes the limited benefit demonstrated by both docetaxel and erlotinib stresses the importance of new drug development in this setting.

Another options, Langer suggests, would be to readminister the initial carboplatin and pemetrexed regimen. This could represent an effective option, particularly if the initial response was high and the treatment was well tolerated, believes Everett E. Vokes, MD. Outside of this, docetaxel would make an excellent choice.

The continuation of bevacizumab after first-line treatment is an established paradigm for patients with colorectal cancer, notes Langer. However, many approaches that work in other disease types have not successfully translated to the management of NSCLC, adds Karen L. Reckamp, MD, MS. As a result of this, to investigate the efficacy of continued bevacizumab specifically in nonsquamous NSCLC, the phase IIIb AvaALL trial was formed and is currently in progress, notes Langer.

Maintenance Therapy for NSCLC: Consensus and Controversy
http://www.thecjcr.org/article/view/860/2079
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预防化疗引起的恶心和呕吐--阿瑞匹坦带来疗效突破
化疗引起的恶心和呕吐（CINV）在临床上很常见，如控制不良将会增加就诊次数、降低化疗依从性、减少化疗次数，甚至使患者拒绝进一步化疗等，严重影响患者的生活质量和抗肿瘤治疗效果。因此，CINV的预防和治疗非常重要。

       回顾CINV近30年来的治疗进展，从1978年前尚无有效止吐处方到1998年5-羟色胺3（5-HT3） 受体拮抗剂联合地塞米松的应用，再到2003年神经激肽1（NK1）受体拮抗剂的上市，临床化疗的止吐效果有了明显改善。但在临床实践中仍存在许多问题，如对CINV的预防性治疗不足、完全控制率低，对迟发性CINV的处理不力，CINV的发生率被低估、止吐指南的执行不乐观等，亟待临床医师高度重视并注重患者的个体化治疗。

急性和迟发性CINV的止吐效果有待提高

        CINV是由化疗引起的恶心呕吐，根据呕吐出现的时间常分为3类，急性（发生在化疗开始后首个24小时以内）、迟发性（发生在化疗开始后至少24小时）和预期性（条件反射，发生于化疗前）。

       化疗药物的种类、剂量和用法等药物因素是影响CINV最重要的决定因素。因此，有效防治CINV需要充分了解各种化疗药物和方案的致吐风险，再针对性的选择止吐方案。《2011 年肿瘤支持治疗多国协会（MASCC）指南》根据化疗方案的致吐风险将其分为高、中、低和极低致吐风险药。关于蒽环类联合环磷酰胺（AC）方案，最新版美国临床肿瘤内科学会（ASCO）指南已将其归为高致吐风险方案。

       自20世纪90年代问世以来，5-HT3受体拮抗剂一直是预防中、高致吐风险化疗方案所致呕吐的有效药物，尤其对于急性CINV的有效率高，且其联合地塞米松可使约70%的急性CINV得到完全缓解（CR、无呕吐或未使用补救治疗），使得5-HT3受体拮抗剂联合地塞米松成为了预防急性CINV的标准治疗方案。然而，5-HT3受体拮抗剂对迟发性CINV的预防作用十分有限。随着药物的发展，虽然第2代5-HT3受体拮抗剂帕洛诺司琼的问世对迟发性CINV的预防作用有了一定改善，但这种优势在高度致吐风险药物引起的呕吐中并不确切。

       有研究表明，在不同类型、不同阶段的CINV反应中，发挥主导作用的神经递质及其受体不尽相同。以顺铂引起的CINV为例，在早期阶段引发CINV的主要神经递质为5-HT，而P物质随着时间的推移逐渐在神经传递中占主导地位，提示临床上可能需要结合作用机制不同的止吐药物才能较好地抑制呕吐。

        由此可见，临床仍有约30%的急性呕吐和约50%的迟发性呕吐尚未得到有效控制，开发新的有效止吐药进一步提高急性和迟发性CINV的CR率成为了化疗止吐药物临床应用关注的焦点。

含阿瑞匹坦的止吐方案显著改善CINV的止呕疗效

       随着对P物质和NK1受体研究的深入，2003年首个获批用于临床的NK1受体阻滞剂阿瑞匹坦为防治CINV提供了强有力的武器。阿瑞匹坦具有全新的药理作用机制，对NK1受体具有选择性和高亲和力，能维持长时间的中枢活性，使急性和迟发性CINV的CR率有了明显提高，尤其使迟发性CINV的控制有了新突破。多项研究结果证实，在5-HT3受体拮抗剂＋地塞米松方案中联合阿瑞匹坦的止吐方案在预防中、高致吐风险化疗方案所致的急性或迟发性呕吐的疗效更佳，且不会明显增加毒性作用。

        2003年两项随机对照临床研究比较了标准止吐方案（昂丹司琼＋地塞米松）±阿瑞匹坦对接受高度催吐性化疗药物（HEC，顺铂≥70 mg/m2）治疗患者CINV的预防作用。结果显示，联合阿瑞匹坦组对HEC导致的急性和迟发性CINV的CR（68%对48%，P＜0.001）和无呕吐率（72%对50%，P＜0.01）显著优于标准止吐组。2011年中国学者开展的高剂量顺铂（≥70 mg/m2）研究亦得出相似结果，阿瑞匹坦＋标准止吐方案（格拉司琼＋地塞米松）对CINV的CR（69%对57%，P=0.007）和无呕吐率（71%对57%，P=0.003）明显高于标准止吐组（图1）。在针对接受AC方案治疗的女性乳腺癌中，阿瑞匹坦联合标准止吐方案在预防CINV的CR（P=0.015）和无呕吐率（P＜0.001）亦显示更优。


       值得一提的是，阿瑞匹坦是细胞色素P450 3A4（CYP3A4）的中度抑制剂，有些化疗药（如环磷酰胺、多西他赛）均是 CYP3A4 的底物，联用时代谢会受影响，疗效和毒性作用是否也受影响？目前研究数据显示，尚无确切证据证明阿瑞匹坦对接受依托泊苷、长春瑞滨或紫杉醇静脉输注患者的安全性有影响，且多西他赛和静脉输注长春瑞滨的药代动力学研究显示有无阿瑞匹坦的曲线下面积（AUC）并无差异。但阿瑞匹坦与口服长春瑞滨或其他主要靠肠壁CYP3A4代谢的口服药联合时，应该慎重。

       基于临床研究结果，2011年MASCC更新的预防CINV指南中，阿瑞匹坦被推荐作为多种止吐方案的用药之一。对于接受高致吐风险药物或AC方案化疗的患者，含阿瑞匹坦的三联方案（5-HT3受体拮抗剂＋地塞米松＋阿瑞匹坦）推荐用于预防急性CINV，阿瑞匹坦联合地塞米松用于治疗迟发性CINV。阿瑞匹坦的推荐使用剂量如下：用于预防急性CINV的剂量为125 mg，化疗当天服用；用于预防迟发性CINV的剂量为80 mg，连续两天口服。

遵循止吐指南用药，提高呕吐控制

       除了药物因素会影响CINV的发生外，非药物因素如性别、年龄、一般状况、酒精摄入耐受量、妊娠期呕吐程度和既往化疗恶心呕吐程度等也可影响CINV的程度。一般而言，年轻、女性、酒量差、既往妊娠呕吐反应重、既往CINV控制不良的患者，发生恶心呕吐的风险增大。有研究显示，老龄、男性、常饮酒、低顺铂剂量均与顺铂化疗低呕吐风险相关；在接受AC方案化疗的女性中，老龄、常饮酒和无妊娠与呕吐低风险相关。临床上，我们能否鉴定出无需使用阿瑞匹坦预防的顺铂或AC方案治疗的低风险人群呢？近年来的研究探讨了这个问题。

       2010年一项研究以顺铂≥70 mg/m2治疗的患者为研究对象，将＞65岁、男性、≥每周5次饮酒或顺铂≤80 mg/m2单一因素定义为致吐低风险，结果发现所有单一因素均不能鉴别患者不会获益于阿瑞匹坦用药。2011年另一项根据存在的危险因素数目分析AC研究的结果发现，包含0个危险因素的患者接受昂丹司琼加地塞米松的无呕吐率达87.5%，但这仅占总人数比例的27%，即只有一项危险因素，至少仍有1/3的患者接受昂丹司琼加地塞米松治疗后仍发生呕吐（图2）。因此，对于接受顺铂或AC方案化疗的患者，2011年MASCC、ASCO、NCCN等多个指南均推荐应用含阿瑞匹坦的止吐方案。


       目前，CINV的确切发病率和临床指南执行仍是临床值得关注的问题。

       2011年8个欧洲国家开展的多中心PEER研究数据显示，遵守指南的化疗预防药物可明显降低患者在中、高度致吐风险化疗方案治疗中出现CINV的比例，但由于CINV 的发病率在欧洲被低估，因此医生没能很好地遵照指南给患者预防用药；同时，亚洲患者中CINV的发病率同样也被低估，指南执行情况亦不客观。

       鉴于CINV的高发生率及对患者治疗依从性、疗效及生活质量的不利影响，亟需遵循指南规范CINV的防治，提高临床止吐效果。

小结

       由此可见，关于化疗止吐，应按照呕吐风险评估分层防治，根据不同化疗药物或方案的致吐风险选择止吐方案。NK1新药阿瑞匹坦自上市以后，为防治CINV提供了强有力的武器，进一步提高了急性和迟发性CINV的止吐效果，同时在包括MASCC、NCCN、ASCO等多个指南中被推荐用于预防中、高度致吐风险药物或方案所致的呕吐。临床上，我们应以循证医学为依据，遵循止吐指南，并结合中国临床实际，作好CINV的规范化、个体化治疗。