How long is long enough?
How long is long enough?
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多长才算足够长呢？
DOI：
10.1200/jco.2010.34.0455
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
A. Seidman
中科院分区：
文献类型：
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作者：
A. Seidman
史密斯女士，一位健康的58岁女性，在您的办公室，她在完成II期乳腺癌辅助化疗三年后，对一个可疑的肺结节进行了计算机断层扫描引导下的穿刺活检。你同情地向她解释，结果证实了转移性乳腺癌（MBC）的诊断，与原发肿瘤一样，缺乏激素和HER2受体的过度表达。史密斯夫人咳嗽，她的咳嗽是在她的计算机断层扫描显示许多双侧肺结节后才出现的。你解释了细胞毒性化疗在缓解癌症方面的作用，改善癌症相关症状，你希望延长生存期。你解释了你计划的化疗方案可能产生的一系列副作用。史密斯太太接着问：“医生，我需要做多长时间的化疗？”根据她的肿瘤内科医生是谁，在某种程度上也取决于地理位置，史密斯夫人可能会得到不同的建议。例如，一位肿瘤学家可能会说，“我们会给你治疗4到6个月，然后停下来观察。如果有需要，我们随时可以再招待您。”另一个可能会说，“你的化疗时间无法提前确定；这取决于你的癌症对治疗的反应以及你对治疗的耐受程度。”是否两种方法都是正确的，或者事实上，只有一个正确的答案？Gennari等人在对MBC一线化疗持续时间的系统回顾和荟萃分析中，在这个问题上更接近于“持续时间越长越好”的立场，尽管有一些重要的警告。他们的荟萃分析是在一组随机试验中进行的，这些试验具有公认的异质设计。研究（11项）和患者（2269例）的数量不大；这很难对我们在辅助设置中所拥有的奢侈程度进行meta分析。相比之下，比较两种一线化疗方案的当代个体随机iii期试验通常招募500至700例或更多患者。与牛津大学的综述不同的是，这个荟萃分析是根据已发表的数据进行的，而不是通过数据进行的。它也脱离了临床实践，因为在没有进展的情况下，肿瘤学家可能会选择继续使用比适用于临床试验的剂量减少规则所允许的低得多的剂量和相当可接受的毒性的药物或方案。尽管有这些考虑，Gennari等人的报告提高了总生存期（OS），具有边际统计学意义(风险比，0.91;95% CI, 0.84 ~ 0.99；046)，分配更长的一线化疗时间。相比之下，无进展生存期的改善更为显著（风险比，0.66;95% CI, 0.60 ~ 0.72; P .001）。考虑到进展后治疗可以影响OS这一看似合理的概念，这是意料之中的；也就是说，接下来的事情很重要。最近的观察结果表明，拉帕替尼加曲妥珠单抗和伊瑞布林在一线治疗之外的情况下延长了生存期，这支持了这一点。一项较早的研究发现，相对缺乏紫杉烷作为二线或后续治疗与随机分配到非紫杉烷一线化疗的患者的生存期较短有关，这应该使我们清醒地认识到，在仅仅检查MBC的多章故事的第一章的试验中，OS作为有意义的终点的局限性。总的来说，这些试验似乎告诉我们，当故事的剩余部分越来越少时，延长单个章节更有可能使故事变得更长。也许在这方面，治疗MBC的二线和三线化疗类似于治疗非小细胞肺癌（NSCLC）的一线化疗。可以肯定的是，许多在这种疾病管理方面经验丰富的肿瘤学家认识到，MBC的生物学和临床行为的异质性比任何试验或荟萃分析都需要更个性化的治疗策略。事实上,oneshoedoesnotfitall英尺。一线化疗的治疗指标——疗效和毒性之间的平衡——是动态的，而不是静态的。化疗早期，通常在前几个周期，患者通常经历肿瘤体积和癌症相关症状最明显的缩小，而累积性治疗相关毒性（如神经病变、疲劳、手足综合征、心肌病）可能会在晚些时候出现，降低治疗指数，需要减少剂量、延迟或中断治疗或治疗假期。尽管这一荟萃分析支持“越长越好”的方法，但这正是医学艺术与医学科学在临床中的交集之处。像史密斯夫人这样的病人在回答化疗持续时间的问题时，可能会听到许多警句，比如“如果没有坏掉，就不要修复它”，或者“乳腺癌的自然历史是不断发展并最终导致死亡的。”如果我们正在改变自然历史而没有不可接受的毒性，我们应该坚持下去”（即，治疗进展）或“治疗不应比疾病更糟”（即，停止并观察毒性是否过高）。我承认我在特定的情况下使用了这些咒语。当前的荟萃分析指出了局限性，确实支持更持续的一线化疗时间。所以假设这些格言是合理的，人们如何在临床实践中满足它们呢？对于her2过表达的MBC患者，基于已证实的生存优势，使用曲妥珠单抗进行一线化疗是相当普遍的做法。当治疗指数缩小时，在最大反应和/或毒性限制点停止细胞毒性化疗成分（通常但不完全是紫杉烷）并简单地继续曲妥珠单抗也是很常见的。《临床肿瘤学杂志》第29卷第16期2011年6月1日
Mrs. Smith, an otherwise healthy 58-year-old woman, is in your office to review the results of a computed tomography–guided needle biopsy of a suspicious lung nodule three years after she completed adjuvant chemotherapy for stage II breast cancer. You empathetically explain to her that the results confirm a diagnosis of metastatic breast cancer (MBC) which, like the primary tumor, lacks hormone and HER2 receptor overexpression. Mrs. Smith coughs a cough that has only developed after her computed tomography scan revealed numerous bilateral pulmonary nodules. You explain the role for cytotoxic chemotherapy in attempting to achieve a remission, improving cancer-related symptoms, and you hope, prolonging survival. You explain the laundry list of possible adverse effects from your planned chemotherapy regimen. Mrs. Smith then asks, “Doctor, how long will I need to be on this chemotherapy?” Depending on who her medical oncologist is and, to some extent, on geography, Mrs. Smith may get different recommendations. For example, one oncologist might say, “We will treat you for 4 to 6 months and then stop and observe. We can always treat you again as the need arises.” Another might say, “The duration of your chemotherapy cannot be determined in advance; it will depend on how well your cancer responds to treatment and how well you tolerate it.” Can both approaches be correct, or in fact, is there only one right answer? In their systematic review and meta-analysis examining the duration of first-line chemotherapy for MBC, Gennari et al inch us a bit closer to the “longer (duration) is better” stance on this issue, albeit with some significant caveats. Their meta-analysis was conducted on a group of randomized trials with admittedly heterogeneous designs. The number of studies (n 11) and patients (n 2,269) is modest; this ishardlyameta-analysisofthemagnitudethatwehavetheluxuryofinthe adjuvant setting. By comparison, contemporary individual randomized phaseIII trialscomparingtwofirst-linechemotherapyregimensforMBC typically enroll 500 to 700 or more patients. Unlike the Oxford overview, thismeta-analysis isconductedonpublisheddata,notrawdata.It is also divorced from clinical practice, given that oncologists may choose, in the absence of progression, to continue a drug or regimen at much lower doses and with quite acceptable toxicity compared with those permitted by dose reduction rules that apply to clinical trials. Despite these considerations, Gennari et al report improved overall survival (OS) of marginal statistical significance (hazard ratio, 0.91; 95% CI, 0.84 to 0.99; P .046) with assignment to longer first-line chemotherapy duration. By contrast, the improvement in progression-free survival is more robust (hazard ratio, 0.66; 95% CI, 0.60 to 0.72; P .001). This is expected, given the quite plausible notion that postprogression therapy can impact OS; that is, that what comes next matters. The recent observations that the combination of lapatinib plus trastuzumab and eribulin prolong survival in settings well beyond first-line therapy support this. An older finding that the relative lack of taxane use as secondor subsequent-line therapy wasassociatedwithshortersurvivalamongpatientsrandomlyassignedto nontaxane first-line chemotherapy should sober us regarding the limitation of OS as a meaningful end point in trials that simply examine chapter one of the often multichapter story of MBC. Collectively, these trials seem totellus that,whenlessof thestoryremainstoberead,prolongingasingle chapter is more likely to make the story longer. Perhaps secondand third-line chemotherapy for MBC resembles first-line therapy for non– small-cell lung cancer (NSCLC) in this respect. To be sure, many oncologists experienced in the management of this disease recognize that the heterogeneity in the biology and clinical behavior of MBC argue for more individualized treatment strategies than anyonetrialormeta-analysiscanaddress. Indeed,oneshoedoesnotfitall feet. The therapeutic index of first-line chemotherapy—the balance betweenefficacyandtoxicity—isdynamic,notstatic.Earlyonduringchemotherapy, typically in the first few cycles, patients usually experience the most obvious reduction in tumor volume and cancer-related symptoms, whereas cumulative treatment-related toxicities (eg, neuropathy, fatigue, hand-foot syndrome, cardiomyopathy) may emerge later on, lowering the therapeutic index and arguing for dose reduction, delay, or a break fromtherapyortreatmentholiday.Althoughthismeta-analysis arguesin favor of the “longer is better” approach, this is the point in the clinic when the art of medicine intersects with the science of medicine. Patients like Mrs. Smith may hear many aphorisms applied in response to the duration of chemotherapy question—such as “If it is not broken, do not fix it,” or “The natural history of breast cancer is to progress and ultimately cause death. If we are altering that natural history without unacceptable toxicity, we should keep at it” (ie, treat to progression) or “The treatment should not be worse than the disease” (ie, stop and observe whether toxicities are excessive). I admit that I employ each of these mantras in selected situations. The current metaanalysis, with the limitations noted, does indeed argue in favor of more sustained duration of first-line chemotherapy. So assuming these aphorisms are reasonable, how can one satisfy them in clinical practice? For the patient with HER2-overexpressing MBC, it is fairly common practice to administer first-line chemotherapy with trastuzumab, on the basis of the demonstrated survival advantage of this approach. It is also quite common to stop the cytotoxic chemotherapy component (commonly, but not exclusively, a taxane) at the point of maximal response and/or limiting toxicity, when the therapeutic index narrows and to simply continue trastuzumab. There are fewer more JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 16 JUNE 1 2011
影响因子：
158.5
作者：
Sandler, Alan;Gray, Robert;Johnson, David H.
通讯作者：
Johnson, David H.