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阻断上皮细胞生长因子接受体(EGFR)来治疗非小细胞肺癌越来越普遍，但是，有关何时开始治疗以及如何筛检病患比较好仍有争议；5月5日在临床肿瘤期刊线上发布的编辑评论认为，可能 — 或许无可避免 —在不久的将来，将有一个检测小组来确认哪些病患可以，以及哪些病患不可能从治疗获利。
但是，编辑人员、多伦多玛格丽特公主医院的Frances Shepherd医师写道，第一线EGFR抑制剂治疗对病患的分子筛选，目前还不是适当时机；这些评论主要是因为一篇新的研究，探索第一线EGFR酪胺酸激酶抑制剂取代化疗的好处；两种口服制剂：erlotinib (Tarceva，Genentech) 和 gefitinib (Iressa，AstraZeneca)，在美国获得核准作为第二线和第三线治疗。
研究发现，将这些制剂加入第一线的全身化疗可以改善反应率和存活率，但是在突变病患出现预料之外的高反应率；因此，许多研究者假设，这些病患或许适合用EGFR酪胺酸激酶抑制剂作为第一线治疗。
【EGFR酪胺酸激酶抑制剂取代化疗？】
同一期的临床肿瘤期刊的另一篇新研究中，研究人员报告他们在34位突变病患使用gefitinib作为第一线治疗的经验，这属于多中心iTARGET试验的一部份。
这些研究人员是由麻州综合医院癌症中心的Lecia Sequist医师领衔，报告指出整体反应率为55%，与其他研究者的结果类似，不过，非典型突变的病患均未达反应。
如同在所有的一系列反应中，突变在女性、一生未抽烟者、肺腺癌病患比较常见。
研究人员观察发现，平均无恶化存活期为9.2个月，整体存活期为17.5个月，病患每天接受250 mg的gefitinib治疗，直到出现恶化或者意料之外的毒性为止。
Shepherd 医师指出，他们的结果类似erlotinib或者 gefitinib用于突变病患的单一组别第二期试验；作者报告指出，病患获得明显的临床利益，且结果是细胞毒性制剂处方用于未经筛选之非小细胞肺癌者效果的两倍。
但是，Shepherd医师认为，未经筛选之非小细胞肺癌者显然不是适合的比较对象。
现在有许多文献指出EGFR突变病患以化学治疗的各种存活率；Shepherd医师指出，不变的是，他们的存活总是明显长于野生型EGFR(wild-type EGFR)病患，且在多篇文献中，平均存活未达两年。
她指出，这件事情告诉我们的是，第一线EGFR 酪胺酸激酶抑制剂治疗突变病患的研究可能都未臻成熟就发表，平均追踪期不到化疗病患预期存活时间的一半，因此，Sequist等人的研究指出的17.5个月平均存活真的可以与历史控制组加以比较吗？
【第一线治疗的研究未臻成熟即发表】
研究指出根据病患之分子资料筛选的可行性，但是Shepherd医师认为，不确定突变病患必须接受第一线EGFR 酪胺酸激酶抑制剂治疗；在确认结论之前，我们必须等待有关化疗和EGFR酪胺酸激酶抑制剂治疗之随机比较研究的存活结果。
Shepherd 医师指出，即使治疗没有比较好的存活率，只有相同或者较差的存活率，这仍是有吸引力的治疗选项，也或许是治疗选择，因为它有比较好的副作用资料。
但是 EGFR 抑制剂有其毒性，如之前Medscape Oncology期刊所报导的，这类药物会引起皮肤、头发、指甲和黏膜改变。
研究人员在去年的欧洲癌症期刊(2007;43:845-851)中指出，分类、病原和一般治疗都会引起不良反应。
荷兰Leiden大学医学中心A. F. Galimont-Collen领导的团队指出，大部分的副作用耐受良好且容易治疗，除了指甲异常之外，会相当疼痛且对治疗无效。
Frances Shepherd医师报告与AstraZeneca和Roche有财经关系。
Tests in the Works to Determin
By Allison Gandey
Medscape Medical News
The blocking of epidermal growth-factor receptors (EGFR) to treat non-small-cell lung cancer is becoming increasingly common, but there is considerable debate about when to initiate therapy and how best to select patients. An editorial published online May 5 in the Journal of Clinical Oncology suggests it is likely — and probably inevitable — that a panel of tests will be used in the not-too-distant future to determine which patients are likely and which patients are unlikely to benefit from therapy.
But, writes editorialist Frances Shepherd, MD, from the Princess Margaret Hospital in Toronto, Ontario, molecular selection of patients for first-line therapy with EGFR inhibitors "is not quite ready for prime time."
The editorial was prompted by a new study exploring the benefit of first-line EGFR tyrosine kinase inhibitors instead of chemotherapy. Two oral agents, erlotinib (Tarceva, Genentech) and gefitinib (Iressa, AstraZeneca), have received approval in the United States for treatment in the second- and third-line setting.
Studies have found that adding these agents to systemic chemotherapy in the first-line setting does improve response and survival rates. But unexpectedly high response rates have been observed in patients with mutations.
As a result, several investigators have hypothesized that it might be appropriate to treat these patients with first-line EGFR tyrosine kinase inhibitors.
Treat With EGFR Tyrosine Kinase Inhibitor Instead of Chemotherapy?
In the new study published in the same issue of the Journal of Clinical Oncology, researchers report their experience with gefitinib in the first-line treatment of 34 patients with mutations. The work is part of the multicenter iTARGET trial.
The investigators, led by Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, report an overall response rate of 55%. This is similar to reports from other investigators, although no patient with atypical mutations achieved a response.
As in almost all series, mutations were seen more frequently in females, lifetime nonsmokers, and patients with adenocarcinoma.
The researchers observed a median progression-free survival of 9.2 months and an overall survival of 17.5 months. Patients were treated with gefitinib 250?mg per day until progression or unacceptable toxicity.
"Their results are similar to those of the other single-arm phase?2 trials of either erlotinib or gefitinib in patients with mutations," Dr. Shepherd notes. The authors report that patients had significant clinical benefit and the results were 2 times greater than typical results with cytotoxic regimens in unselected non-small-cell lung cancer populations.
But Dr. Shepherd argues that the unselected non-small-cell lung cancer population is definitely not the appropriate comparator.
There have now been several publications in which the survival rates of patients with EGFR mutations treated with chemotherapy have been reported. "Invariably," Dr. Shepherd points out, "their survival has been significantly longer than that of patients with wild-type EGFR, and in several publications, the median survival has not been reached at 2 years."
The first thing that this tells us, she notes, is that the studies of first-line EGFR tyrosine kinase inhibitor therapy in mutation-positive patients likely have all been published prematurely, with median follow-up times less than half the expected survival time of patients treated with chemotherapy. "With this in mind, does the 17.5-month median survival in the Sequist et al study really compare favorably to historical controls?"
Studies of First-Line Therapy Published Prematurely
The study demonstrates the feasibility of selecting patients on the basis of their molecular profile, but Dr. Shepherd suggests that it does not confirm that patients with mutations should be treated with a first-line EGFR tyrosine kinase inhibitor.
"Before this conclusion can be reached, we must await the survival results from randomized studies comparing chemotherapy to EGFR tyrosine kinase inhibitor therapy."
Dr. Shepherd adds that even if therapy does not result in superior survival, equivalent or noninferior survival rates would still make this an attractive treatment option, or possibly the treatment of choice, in view of its favorable adverse-effect profile.
But EGFR inhibitors do have toxicities. As previously reported by Medscape Oncology, the drugs are said to cause skin, hair, nail, and mucosal changes.
Researchers reporting last year in the European Journal of Cancer (2007;43:845-851) outlined the classification, pathogenesis, and treatment of common therapy-induced adverse effects.
"Most of the side effects are well tolerated and are easily treatable," reported the group, led by A. F. Galimont-Collen, from the Leiden University Medical Center in the Netherlands, "except for nail disorders, which can be very painful and resistant to therapy."
Dr. Frances Shepherd reports having financial ties to AstraZeneca and Roche.