癌症治疗

　　Taking aim sooner

　　即将实现对症下药

　　If personalised medicine is to achieve its full potential, it should be used earlier on in clinical trials

　　若想让个体化药物发挥最大潜力，那就应该尽早将它投入临床试验。

　　Jun 9th 2011 | from the print edition

　　ONE of the prospects supporters of the Human Genome Project held out was personalised medicine. Knowing which genes were involved in a particular patient’s disease would allow drugs to be deployed with greater precision. That is starting to happen in the field of cancer. Several targeted therapies, aimed at specific cancer-causing mutations, including Gleevec for chronic myelogenous leukaemia and Herceptin for some types of breast cancer, have been spectacularly successful. Yet in most cases of cancer doctors still base their treatment on where in the body a tumour has sprung up, rather than on which molecular aberrations have caused it.

　　人类基因组计划支持者认为该计划的前景之一就是个体化药物。通过了解哪些基因与特定病人的疾病存在关联，会使药物的使用更加精确。在癌症领域，这种情况即将成为现实。几种针对特定致癌突变的靶向疗法——包括治疗慢性髓细胞性白血病的格列卫和治疗多种类型乳癌的赫塞汀——所展现出的治疗效果令世人瞩目。而在癌症的大多数病例中，医生们的治疗仍然基于人体中肿瘤出现的位置，而不考虑究竟是哪几种分子畸变导致了肿瘤的发生。

　　The same is true of medical researchers recruiting volunteers for clinical trials, especially those known as phase I trials, in which a new drug is tested on people for the first time. Participants in such trials are often those whose tumour has spread beyond its original site, and will probably prove fatal. Usually, they have tried all proven therapies, to no avail. Their precarious condition means they are rarely accepted for phase II and III trials, which are more complicated and extensive.

　　对于招募临床试验志愿者，尤其是所谓的第一阶段试验（在该阶段，人们要接受新药的第一次人体试验）志愿者的医疗研究员来说，情况也同样如此。该阶段试验的参加者通常是那些肿瘤发生扩散而远离初始位置的人，他们也将因此而有性命之忧。一般来说，他们已然尝试过所有经过验证的疗法，却徒劳无功。他们危急的病情意味着只有少数人能接受更为复杂和广泛的第二和第三阶段试验。

　　Oddly, though, even if the drug being tested is a targeted therapy the tradition in phase I trials has been to gather together patients with, say, lung cancer and assume that all carry the relevant mutation. That is because such trials are concerned mainly with testing a drug’s safety, not its efficacy. The volunteers are usually happy to go along with this. But the odds are not good. On average, fewer than 5% of participants in phase I trials respond successfully to the treatment.

　　但是令人感到奇怪的是，即便所试验的药物是一种靶向治疗药物，第一阶段试验的传统也一直是招募病人，比如肺癌患者，并假定他们所有人都携带相关的突变体。那是因为这些试验主要关注点在于测试药品的安全性，而非有效性。志愿者通常愿意从头到尾全程配合，但是效果仍不甚理想。平均来说，在第一阶段试验中只有不到5%的参与者经过治疗后病情大有起色。

　　Many scientists think this approach is a wasted opportunity. They believe that matching volunteers’ genetic profiles to the drugs being tested will not only be better for the volunteers, but may also speed up the trials, and save millions of dollars in the process. One such is Apostolia-Maria Tsimberidou of the University of Texas’s MD Anderson Cancer Centre, in Houston. And her preliminary results, presented this week at a meeting of the American Society of Clinical Oncology in Chicago, suggest she is right.

　　许多科学家认识到，这种方法其实是在走弯路。他们认为将志愿者的基因指纹与被试验药物进行匹配，不仅更有利于志愿者，而且也可能加快试验进程，节约数百万美元的试验经费。Apostolia-Maria Tsimberidou来自得克萨斯大学位于休斯敦的MD安德森癌症中心，也抱有相同的看法。她本周在芝加哥的美国临床肿瘤学协会会议上发表的初步研究结果，表明她所言非虚。

　　On target?

　　击中要害？

　　Dr Tsimberidou and her colleagues selected volunteers with late-stage cancer whose tumours were caused by single, known mutations and did the equivalent of a phase I trial on them. In the case of the 175 volunteers for whose mutations a targeted therapy existed, it was given. The remaining 116 received traditional treatment. Of those in the targeted-trial group, 29% responded positively to the therapy. (The tumours of four disappeared altogether.) Only 5% of those on untargeted drugs showed improvements—precisely in line with the historical figure. Those on targeted drugs also responded for longer than those who were not (five months, as against two months, on average). And they lived for 13 months compared with nine.

　　Tsimberidou博士和她的同事挑选了患有晚期癌症的志愿者（这些患者的肿瘤是由单一的、已知的突变引起的），试验方法与第一阶段相同。按照规程，175名志愿者都接受了针对其基因突变的靶向疗法试验。余下的116名志愿者接受了传统治疗。在靶向试验组中，29%的被试验者疗效显著（四个人的肿瘤完全消失）。在传统治疗组中，只有5%的被试验者病情有所好转——与历史数据正好吻合。经过靶向药物治疗的患者对治疗产生有效反应的时间（平均5个月）也比传统治疗患者（平均2个月）更长。他们存活时间为13个月，而传统治疗患者只有9个月。

　　Dr Tsimberidou cautions that the data, though encouraging, need to be qualified. Since her patients were not assigned to the targeted and untargeted groups at random, the gold standard for clinical trials, some hidden variable, rather than the treatment, may explain the different outcomes. The untargeted group might, for example, have been sicker to start with. They did, indeed, have higher initial levels of lactate dehydrogenase, an enzyme associated with tissue breakdown, so this possibility should not be discounted. However, those on targeted therapy did better, compared with their reactions to previous treatments, than those who were not.

　　Tsimberidou博士提醒说，尽管数据令人振奋，但仍需要对数据进行修正。既然她没有将病人按照临床试验的黄金法则随机分配到靶向治疗组和非靶向治疗组，那么某些隐含变量，而非治疗本身，可能导致了不同的结果。例如，非靶向治疗组在一开始可能病情更为严重。在开始的时候他们的乳酸脱氢酶（它是一种与组织衰竭有关的酶）水平确实偏高，因此这种可能性必须予以考虑。然而那些进行靶向治疗的人比他们先前治疗时的效果更好，而那些未进行靶向治疗的人和先前治疗时相比没有变化。

　　Not surprisingly, drug companies are taking an interest in the findings. If a hefty proportion of patients in an early trial show a robust response to a drug, its developer may be able to skip phase II, the first real look at a drug’s pharmacological credentials, and jump straight to a phase III trial—the ultimate test of efficacy. This might save a company several years of clinical studies, and an awful lot of money.

　　不出意料，药品公司对这项研究结果很感兴趣。如果在早期试验中，有大量病人对药物反应良好，那么该药的开发者就可能越过第二阶段（对药物药理学功效的第一次真正意义上的评判），直接跳到第三阶段试验——药效的最终试验。这将为一个公司节约数年临床研究时间和一大笔钱。

　　Widespread adoption of the new approach may, however, be difficult. Tests to detect cancer-causing mutations are still in their infancy. Many such mutations have not yet been identified, and even when a known mutation is found in a tumour, drugs to block its effects may be unavailable. On top of that, many patients will not participate in a trial that requires the collection of an additional sample from their tumour, for this is an invasive, painful and potentially dangerous procedure. Indeed, one in ten of the applicants for Dr Tsimberidou’s trial was unable to provide samples which could be tested for their molecular make-up.

　　而要想广泛采用新方法可能是困难的。用以检测致癌突变的化验手段还停留在开始阶段，许多这种突变还没有被识别出来，况且即使在肿瘤上发现一种已知的变异，而阻止该变异发生作用的药物可能还没有研制出来。除此之外，如果需要从病人的肿瘤中额外地取样的话，许多病人就不会再参加试验了，因为这种外科手术容易导致肿瘤扩散、疼痛和潜在的危险。果然，Tsimberidou博士试验的申请者每十个就有一个不能提供试样，以测定其分子组成。

　　However, Johann de Bono and his colleagues at the Royal Marsden Hospital, in London, think that they have found a solution to this problem. Rather than probe tumours directly, they can test bits of tumour DNA that float in the bloodstream, and identify genetic mutations in this way with nearly the same accuracy as the direct method provides. If these preliminary results are confirmed, more patients with advanced cancer will have been offered a tantalising glimmer of hope.

　　然而伦敦皇家马斯登医院的Johann de Bono和他的同事认为，他们找到了解决该问题的方案。他们并没有采取直接穿刺肿瘤的方式，而是通过检测血流中漂浮的少量肿瘤DNA，就能识别出基因突变，这种方式与直接法相比在精确性上几乎相同。如果这些初期结果得到确证，更多罹患晚期癌症的患者将会看到一线鼓舞人心的希望。