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前列腺癌的个性化治疗

更新时间:2014-1-29 14:40:58 来源:华尔街日报中文网 作者:佚名

Custom-Fit Treatments for Prostate Cancer
前列腺癌的个性化治疗

In a bid to improve treatment for men with high-risk prostate cancer, some researchers want to take a page from the playbook for breast cancer.

Medical scientists are working to develop strategies for treating prostate tumors that are tailored to individual patients, as is currently done for many women with breast cancer. Fresh advances in the understanding of prostate cancer suggest that some men with a high-risk form of the disease might benefit from more aggressive treatment.

Other men may benefit from less treatment. For instance, radiation plus hormone therapy, also called androgen-deprivation therapy, is a common strategy to kill prostate tumors. But a recent study from researchers at Memorial Sloan-Kettering Cancer Center suggests that analyzing a tumor's DNA may identify patients who would do just as well with radiation alone. If borne out in further research, some men may be able to skip hormone therapy, avoiding side effects that include loss of libido and heart disease.

The developments come amid changes in the way many types of cancer are identified and treated. The changes are being driven in part by the use of genomic information that defines tumors by their underlying biology and provides clues about drivers of the disease not available by conventional exams.

Researchers say, for instance, that several new genomic prostate-cancer tests can help separate high-risk tumors from those at low or intermediate risk, offering information to doctors and patients to guide treatment choices.

About 240,000 men in the U.S. are diagnosed with prostate cancer each year. Most cases are low-risk forms of the disease that will have little effect on their lives or longevity. In these cases, a big concern is that overtreating the cancer puts these men at unnecessary risk for impotence, incontinence and other complications.

About 20% of diagnosed men are considered at high risk for having their cancers spread beyond the prostate gland based on a measure called the Gleason score and other factors. For some with an aggressive form of the disease, the 10-year-survival rate is well below 50%. 'We may not be treating them aggressively enough,' says William Polkinghorn, a radiation oncologist at Memorial Sloan-Kettering, in New York.

Some 95% of men who die of the disease are initially diagnosed with cancer that is confined to the prostate region, says Philip Kantoff, director of the Lank Center for genitourinary oncology at the Harvard-affiliated Dana-Farber Cancer Institute, in Boston. Finding ways to 'cure' such patients is 'mission central,' he says. Once cancer spreads beyond the prostate it is considered incurable.

The current standard of care for high-risk prostate cancer is either surgery to remove the cancerous gland or radiation plus hormone therapy to kill the tumor. Some men get radiation after surgery, but generally the two approaches aren't given together.

By comparison, women with high-risk breast cancer, which like prostate cancer is also typically fueled by sex hormones, typically get a combination of surgery, radiation and drugs. Medicines are tailored to patients based on whether the hormones estrogen and progesterone or a gene called HER2 is fueling the tumor.

Aggressive treatment of these women has resulted in improved survival and relapse rates, says Charles Sawyers, head of the human oncology and pathogenesis program at Memorial Sloan-Kettering. Whether a similar approach would improve survival for high-risk prostate cancer isn't certain but it is 'a conversation that needs to be had in a more vigorous way,' he says.

There is some evidence it could work. Research from clinical trials, for instance, suggests that giving radiation soon after surgery increases the time a patient lives without the disease coming back, says Adam Dicker, head of radiation oncology at Jefferson Medical College of Jefferson University, in Philadelphia.

But there have been few studies looking at the effect of combining treatments. It can take 10 to 15 years to complete a trial testing a multipronged strategy versus a single-treatment approach. 'People are hesitant to do those studies because they take such a long time to read out,' Dana-Farber's Dr. Kantoff said.

Genetic tests have recently become available that examine tumors for molecular signatures that predict whether a tumor is high- or low-risk and can help doctors make treatment decisions.

A test marketed by San Diego company GenomeDx Biosciences Inc. yields a molecular profile that can indicate, for instance, whether a man who undergoes prostate surgery to remove the tumor would also benefit from radiation treatment, says Doug Golginow, the company's chief executive.

It 'doesn't tell you if a specific chemotherapy' will work against the tumor, but 'it sorts out a lot of confusion by telling you whether you have the kind of disease that's going to kill you or not kill you,' he says.

Genomic Health Inc., in Redwood City, Calif., and Myriad Genetics Inc., of Salt Lake City, sell tests that, for instance, can help distinguish between high- and low-risk prostate cancers, possibly enabling men to delay or forgo aggressive treatment.

Dr. Polkinghorn's research at Sloan-Kettering yielded another genetic signature that could tell men when they need less therapy.

He led a recent study that showed androgen's role in prostate cancer goes beyond providing fuel for the tumor's growth; the male sex hormone also activates androgen receptors that turn on genes which repair damaged DNA. The finding is important because radiation kills tumor cells by breaking DNA. It also explains a two-decade-old mystery over why combining radiation with anti-androgen drugs is significantly more effective against high-risk cancer than radiation alone.

Depriving the tumor of androgen 'takes the sunscreen off the prostate cancer cell and makes it more sensitive to radiation,' Dr. Polkinghorn says. The report was published in November in the journal Cancer Discovery.

The analysis revealed levels of androgen-receptor activity vary widely among patients. This suggests patients with high androgen activity may benefit from hormone therapy while those with low activity levels may gain little from it and could forgo the treatment. The researchers aim to validate the result by testing it on a database of prostate-tumor specimens gathered from a variety of trials where the outcomes of the patients are known.

Dr. Polkinghorn now runs a clinic for high-risk prostate-cancer patients. He and his colleagues are developing a protocol to test how well such patients respond to more aggressive therapy.

Howard Bellin, a 77-year-old recently retired plastic surgeon who had surgery to remove his cancerous prostate in October, is being treated with the approach. The conventional approach, Dr. Bellin says, is for doctors to wait after surgery to see if the tumor comes back and then 'go after it with bigger guns' or hormone therapy. He says he is being treated now with two hormone drugs and radiation, hoping that a cure lies in 'treating it with your big guns right away.'

为改善对患有高风险前列腺癌男性的治疗疗效,一些研究人员希望从乳腺癌治疗方法借鉴经验。

医学家正努力研究针对每位病人个性化前列腺肿瘤的治疗方法,目前这一做法在患乳腺癌的女性治疗中应用广泛。对前列腺癌的最新进展显示,一些患有高风险前列腺癌的男性可能会从更为积极的治疗中受益。

而对其他人来说,更少的治疗可以带来更好的疗效。举个例子,放射加激素疗法,也被称为“雄激素阻断治疗”是杀死前列腺肿瘤的常用方法,但纽约纪念斯隆-凯特琳癌症中心(Memorial Sloan - Kettering Cancer Center)研究人员近期的一项研究表明,通过分析肿瘤的DNA可以识别出哪些病人只用放射性治疗也能达到相同效果。若能经过进一步研究证实,则一些病人可能无需接受激素治疗,因此也可以避免性欲减少或心脏病等副作用。

上述改进的出现正值多种癌症的识别和治疗方式发生改变之际。之所以出现这些改变,一部分是因为染色体信息的应用,这些信息能够根据肿瘤的潜在生物特性对其确诊,同时也为传统检查无法检测出的疾病诱因提供了线索。

例如研究人员称,不少新的染色体前列腺肿瘤检查可以将高危风险肿瘤与中、低风险肿瘤分离出来,以此为医生和患者提供选择治疗的依据。

每年美国约有24万名男性被诊断出患有前列腺癌,多数为低风险病例,对其生活及寿命没有太大影响。这种情况下的一个重要问题是,过度治疗将使病人置于阳痿、失禁及其他并发症等不必要的风险之中。

根据格里森评分(Gleason score)及其他因素的一种检测,大概20%被诊断出前列腺癌的男性因其癌症已扩散至前列腺以外的部位而被认为具有高危风险。对于患有侵袭性肿瘤的人来说,10年的存活率远低于50%。纪念斯隆-凯特琳癌症中心的放射肿瘤学家威廉·波尔金霍恩(William Polkinghorn)称,可能我们的疗法还不够积极。

哈佛大学医学院附属丹娜-法伯癌症研究院(Dana-Farber Cancer Institute)位于波士顿,其兰克泌尿肿瘤中心 (Lank Center for genitourinary oncology) 主任菲利普·坎托夫(Philip Kantoff)表示,约95%因患此病而死的人最初诊断时肿瘤只限于前列腺部位。他说,找到办法治愈此类病人是“核心任务”。一旦肿瘤扩散到前列腺以外区域,则被认为无药可救。

目前,对高危前列腺癌的常规治疗方法,不是通过手术切除患有癌症的腺体,就是用放射加激素疗法杀死肿瘤。有些人在手术后还接受放射治疗,但一般这两种方法并不同时使用。

相比之下,患有高危乳腺癌的女性通常会采用手术、放射及药物治疗相结合的疗法。根据每个人的肿瘤是由雌激素和孕激素或者一种叫做HER2的基因诱发,病人服用的药物各不相同。乳腺癌和前列腺癌一样,一般由性激素诱发。

纪念斯隆-凯特琳癌症中心人类肿瘤学和发病机制项目负责人查尔斯·索耶斯(Charles Sawyers)说,对女性患者的积极治疗令其存活率和复发率均有所改善。他说,类似方法是否能改善高危前列腺癌症的存活率还不能确定,但“两种癌症间的经验借鉴应该更加活跃”。

有证据显示类似方法是能起到作用的。费城托马斯·杰斐逊大学(Jefferson University)杰斐逊医学院(Jefferson Medical College)放射肿瘤系主任亚当·迪克尔(Adam Dicker)举例说,临床试验研究表明,接受手术之后不久就接受放射治疗增加了病人的寿命,同时减少了复发的可能。

但目前还没有多少研究课题关注复合疗法的疗效。完成对多管齐下的复合疗法和单一疗法对比的初步试验可能需要10到15年时间。达娜-法伯癌症研究院的坎托夫医生说:“因为获得结果的时间很漫长,所以人们不愿意进行这些研究。”

近来已经可以做基因检测来检查肿瘤的分子特征,这些特征可以预测肿瘤是属于高风险还是低风险,还能帮助医生做出诊疗决定。

例如, 地亚哥(San Diego)的公司GenomeDx Biosciences Inc.的首席执行官道格·哥尔基诺(Doug Golginow)表示,该公司推广的一项测试能检测出癌症分子特征,这些特征预示做了前列腺肿瘤切除手术的人是否将从放射治疗中获益。

他说,该测试并不告诉你哪一种化疗会对肿瘤起作用,但它能帮你排除疑惑,告诉你所患的癌症是否致命。

再比如加州雷德伍德城(Redwood City)的Genomic Health Inc.和盐湖城(Salt Lake City)的Myriad Genetics Inc.出售能帮助辨别高、低风险前列腺癌的检测,可使病人推迟或者不采取积极治疗法。

纪念斯隆-凯特琳癌症中心波尔金霍恩博士的研究还发现了另一种基因特征,可以辨别哪些病人不需要接受那么多治疗。

最近由他主持的一项研究揭示,雄性激素在前列腺癌中的作用不仅仅是作为肿瘤增大的诱因;雄性激素同时激发雄激素受体,进而启动可以修复损伤DNA的基因。这项发现很重要,因为放射线通过破坏DNA结构来杀死癌细胞。这也解开了一个长达20年之久的谜,即为什么治疗高危癌症时,放射治疗和抗雄性激素药物结合的方法比单纯放疗更加显著有效。

波尔金霍恩医生说,去除雄性激素肿瘤相当于去掉前列腺癌细胞的防晒霜,使其对放疗更敏感。这份报告于去年11月份在医学期刊《癌症发现》(Cancer Discovery)上发表。

这份分析报告显示,病人的雄激素受体活动水平差别很大。研究表明,雄激素受体活动水平较高的病人可能从激素疗法中受益,而活动水平低的病人不会有太大疗效,可以放弃这种疗法。研究人员计划验证这一结果,方法是对已查明病情的病人进行一系列试验,在试验收集的前列腺肿瘤标本数据库进行测验。

波尔金霍恩医生现在负责一家高危前列腺癌的诊所运营。他和同事们正在拟定章程,以测试病人对更积极疗法的反应如何。

现年77岁,刚刚退休的整形外科医生霍华德·贝林(Howard Bellin)于去年10月份通过手术切除了他患有癌症的前列腺,目前正在接受新疗法。贝林医生说,传统疗法是要医生在手术后观察肿瘤是否会复发,然后再采用更积极的疗法或激素疗法。他说,他目前服用两种激素药物并接受放疗,希望“直接上猛药”可以找到治愈这一癌症的妙方。

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