非小细胞肺癌（NSCLC）的化疗宝典

Maintenance Therapy for NSCLC: Consensus and Controversy
http://www.thecjcr.org/article/view/860/2079
Maintenance Therapy for NSCLC Consensus and Controversy.pdf (513.04 KB, 下载次数: 225)

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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。

ASCO止吐药临床实践指南
新指南推荐：

　　蒽环类联合环磷酰胺应被归为重度致吐性化疗方案。

　　对于接受重度致吐性药物化疗的患者，应给予一种5羟色胺3(5-HT3)受体拮抗剂、地塞米松和一种神经激肽1(NK1)受体拮抗剂治疗。

　　一项大型研究证明福沙匹坦和阿瑞匹坦有相同止吐效果。

　　对于接受中度致吐性药物化疗的患者，应优先给予帕洛诺司琼而非其他药物，并联合地塞米松治疗。

　　对于接受轻度致吐性药物化疗的患者，应在化疗开始前给予地塞米松。

　　对于接受重度致吐性放疗的患者，应在每次放疗前并在放疗后24小时给予患者5-HT3受体拮抗剂，可在第1～5次放疗期间给予患者1疗程共5日的地塞米松治疗。

　　指南更新委员会强调应在治疗过程中持续监测患者症状。医生常低估恶心的发生率，这一症状不如呕吐好控制。

福沙匹坦是阿瑞匹坦的前体药物，注射后在体内迅速转化成阿瑞吡坦。福沙匹坦和阿瑞匹坦有相同止吐效果。
止吐效果：福沙匹坦=阿瑞匹坦>帕洛诺司琼>格拉司琼>昂丹司琼>胃复安
注：阿瑞匹坦Aprepitant（商品名:止敏吐胶囊、Emend）
帕洛诺司琼，格拉司琼，昂丹司琼，胃复安均有口服和静脉剂型；福沙匹坦只有静脉针剂，阿瑞匹坦只有口服剂型。

帕利夫明Palifermin(商品名Kepivance 凯望斯美国Amgen公司)
Amgen公司2004年12月15日宣布FDA已批准了Kepivance(palifermin)用于治疗严重口腔溃疡，而这种口腔溃疡可能会发生在服用过高剂量化疗又接受了骨髓移植的血癌病患者身上。该药用于非血癌患者上的有效性和安全性还正在进行中。
    在双盲临床试验中，血癌患者在接受高剂量化疗加放射治疗前，被随机静注60mμg·kg-1· d-1(n=106)或安慰剂（n=106），共3d。接着患者接受骨髓移植，并被再给予3d的kepivance或安慰剂。最严重的口腔溃疡（4级）发生率在kepivanc组（20%）比安慰机组中（62%）降低了3倍，3~4级溃疡发生率也减少大约1/3（63%比98%）。Kepivanc缩短溃疡疼痛时间（2~4级）达1周之多（8 d比安慰机组的14 d）。研究发现被kepivanc治疗的患者显著减少了口腔和喉头红肿，吃，喝、吞咽和说话能力都有显著改善。此外，接受kepivanc的患者要求吗啡止痛的时间也比安慰机组少（7d比11d）。
kepivanc是一种重组人体角质化细胞生长因子，它通过保护口腔和喉部表皮细胞免遭化疗和放疗的损害而减少溃疡的发生，并可刺激新的表皮细胞在溃疡伤面的生长和发肩。Kepivanc的安全性的耐受性较好。不良反应为皮疹、瘙痒、皮肤红肿、皮肤异常感、口/舌感紊乱，但均为轻微或中度，且短暂。

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Use Glutamine To Reduce The Severity Of Mucositis And Neuropathy (During Chemotherapy Or Radiation Therapy)
If you are about to start a course of chemotherapy that can cause mucositis (i.e. of the mouth, throat or esophagus) or peripheral neuropathy (i.e. hands and feet), ask your oncologist if you can use glutamine to help reduce the severity of these common symptoms.
If you are going to receive radiation therapy to the head, neck or chest (specifically, anywhere near the esophagus), Glutamine can be helpful to reduce the development of severe mucositis in these tissues.
**Did you know that honey is also a proven therapy for mucositis? Read my previous blog entry on honey and mucositis.**
HERE ARE THREE COMMONLY USED REGIMENS IN THE PREVENTION OF MUCOSITIS (ORAL, THROAT OR ESOPHAGEAL) AND PERIPHERAL NEUROPATHY:
You can buy glutamine (usually in the form of L-glutamine), in powder, capsule, tablet, or liquid form. However, I recommend using the powder form of L-glutamine, and mixing it in with cold or room temperature liquids (water or juice.) It should not be added to hot beverages because heat destroys glutamine. Glutamine therapy works best if started at the time of beginning radiation therapy or chemotherapy. It will be less effective if you start this after already showing signs or symptoms of mucositis or peripheral neuropathy.
For the prevention of oral mucositis (OM)
Mix 10 grams of powdered glutamine in a small glass (6-8 ounces) of water or juice. Swish and gargle for 30-60 seconds and swallow. You can continue to do this until the 6-8 ounces are gone. Repeat every 8 hours (schedule: morning, mid-day, evening)
Start this regimen on the first day of chemotherapy and continue for 14 days after the last dose of chemotherapy in patients who do not develop OM or until 5 days after resolution of OM for patients who experienced OM.
Other recommendations:
Refrain from eating or drinking for 30 minutes after dosing.
Adhere to good oral hygiene practices and gently brushed their teeth twice daily, 30 minutes or more after using glutamine, using a soft toothbrush and fluoride toothpaste.
Daily flossing and an alcohol-free fluoride rinse is recommended.
This is based on a study that showed a significant reduction in OM among patients using oral glutamine.
These investigators used a proprietary glutamine suspension (Saforis, MGI Pharma, Inc., Bloomington, MN), which was administered at a dose of 2.5 g per 5 mL 3 times per day for a total daily dose of 7.5 g. This product reportedly is able to be better absorbed into the oral mucosa than standard glutamine. (I believe that this can be compensated for by using a higher dose, 10 grams, 3-times per day, of standard glutamine, as recommended above.)
Various chemotherapy regimens used in this study (21-day cycle): cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF); 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC); or doxorubicin and cyclophosphamide (AC).
Compared with placebo, glutamine significantly reduced the incidence of moderate-to-severe OM 39% vs. 50% (placebo.)
For prevention of mucositis of the throat and esophagus (esophagitis) from radiation and chemotherapy:
Mix 10 grams of powdered glutamine in a small glass (6-8 ounces) of water or juice. Drink (swallow). Repeat every 8 hours (schedule: morning, mid-day, evening)
Start this regimen 1 week before radiation therapy and continue for 2 weeks after completion of radiation therapy.
This is based on a study that showed a significant reduction in esophagitis among patients receiving this regimen versus no glutamine:
There was minimal-to-no-esophagitis was seen in 71% of the glutamine supplemented patients versus only 44% without glutamine
By the end of treatment, the glutamine supplemented patients gained 2.6 kg (median), while those without glutamine lost 3.3 kg (median)
There was a significant delay to the time of first noticing esophagitis in the glutamine patients versus the non-glutamine patients: 25 days versus 16 days.
There were also fewer treatment breaks, hospitalizations and late esophageal toxicities among the patients who took glutamine versus those who did not.
Importantly, there were no differences in cancer recurrence rates at 24 months of follow-up (the glutamine did not reduce the effectiveness of treatment.)
For the prevention of chemotherapy-induced peripheral neuropathy (studied with oxaliplatin and paclitaxel)
Mix 15 grams of powdered glutamine in a small glass (6-8 ounces) of water or juice. Drink. Repeat every 12 hours (schedule: morning and evening)
Start this regimen on the day of oxaliplatin infusion and continue for seven days thereafter. Repeat with each infusion.
This is based on a study that showed a significant reduction in chemotherapy-induced peripheral neuropathy among patients receiving this regimen versus no glutamine:
After all 6 cycles of chemotherapy, 48% of patients in the glutamine group had no peripheral neuropathy (PN) versus only 27% in the non-glutamine group.
After all 6 cycles of chemotherapy, 12% of the patients in the glutamine group had moderate-to-severe PN versus 32% in the non-glutamine group.
Glutamine supplementation significantly improved cold intolerance and lessened the interference to activities of daily living.
Chemotherapy dose-reductions were less frequently needed in the glutamine patients (7%) versus those not taking glutamine (27%)
There were no differences found in the response to chemotherapy or survival between the two groups.
HOW DOES GLUTAMINE REDUCE MUCOSITIS AND ESOPHAGITIS?
Glutamine has been shown to reduce the degree of mucositis through:
anti-inflammatory mechanisms (inhibition of one of the main switches that turn on inflammation, NF-kappaB)
inhibition of bacterial toxins
increased tissue healing (increased fibroblast and collagen synthesis.)
HOW DOES GLUTAMINE REDUCE CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY?
We don’t know exactly, however it is believed that glutamine may exert its neuroprotective effects by upregulation of nerve growth factor. In animal studies, supplementation with glutamine appears to increase NGF.

IS GLUTAMINE SAFE TO GIVE TO PATIENTS WITH CANCER?
This is an area of controversy, as it is well-known that under certain circumstances cancer cells use glutamine for energy even more voraciously than glucose.
However, no human study, have ever shown that glutamine increased tumor growth rates or decreased the efficacy of other cancer therapies.
Over the last 20 years, 36 clinical studies have demonstrated the tolerance, safety and effects of glutamine (oral and IV) in patients undergoing chemotherapy and/or radiation therapy. In each of these studies, researchers have reported that glutamine supplementation in cancer patients improves their metabolism and clinical situation without increasing tumor growth.
Potential Side Effects and Drug Interactions:
Generally, very well-tolerated and is considered safe for use by most people for the duration of cancer care (chemotherapy and/or radiation therapy) in doses up to 40 grams per day (adults.)
Do not use glutamine if you:
Have kidney failure, kidney dysfunction, or if your kidney function is impaired or abnormal.
Have liver failure, liver dysfunction, or if your liver function is impaired or abnormal.
Have ever been diagnosed with or had a period of hepatic encephalopathy (liver function that affects your mental, emotional, or cognitive state).
Have a history of mental illness, especially bipolar depression (manic depression), mania, or hypomania.
Have a history of seizure disorders, such as epilepsy or are taking medications to control a seizure disorder.
Have a history of allergic reaction to monosodium glutamate (MSG), a flavoring agent sometimes used in the preparation of Chinese food in restaurants.
Are taking or have been prescribed to take a medication called lactulose.
Adverse drug-glutamine interactions are not common, but (as with any supplement) always check with your physician before starting glutamine.

1.不建议使用复方氯己定含漱液（Chlorhexidine）用来预防和治疗口腔炎，临床试验显示无益处。
2.推荐使用0.9%生理盐水，有条件可使用Benzydamine (Difflam)漱口液，用软牙刷刷牙。
3.推荐使用左旋谷酰胺（L-glutamine）粉末，有条件者可使用Aesgen公司的左旋谷酰胺(L-glutamine，Saforis)嗽口液。
剂量：将10-15克左旋谷酰胺溶于180-240ml水或者果汁中，1天分三次服用（三餐前15分钟）。
疗程：放化疗前一周和放化疗周期内。
4.头颈部肿瘤放疗可以使用帕利夫明Palifermin(商品名Kepivance 凯望斯美国Amgen公司)，是一种重组人角化细胞生长因子(keratinocytegrowthfactor,KGF)，最近被证明可以有效的减少大剂量化疗诱发的口腔黏膜炎的发生。


Jarrow Formulas, L-Glutamine, 17.6 oz (500 g) Powder $25.97 ￥158.25

（3）化疗开始前2天，结束后2天内禁用升白针。

马哥，我们主治大夫经常在化疗前一天和后一天立即用升白针，有什么危害吗？

PLOS ONE: Combination of EGFR-TKIs and Chemotherapy as First-Line Therapy for Advanced NSCLC: A Meta-Analysis
http://www.scoop.it/t/focus-on-lung-cancer
The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR–TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR–TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data.  Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR = 0.81, 95% CI 0.69–0.95, P = 0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P = 0.02). In selected patients by EGFR-mutation, both mutation positive (HR = 0.48, 95% CI 0.28–0.83, P = 0.009) and negative (HR = 0.84, 95% CI 0.72–0.98, P = 0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P = 0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR = 0.51, 95% CI 0.35–0.74, P = 0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status.