AACR2013：他汀防治癌症的证据仍然不足

广泛应用的降胆固醇药物他汀类能否在癌症治疗中发挥作用？本周召开的美国癌症研究学会年度会议上公布的三项新研究给出了肯定的回答。研究者报道说，他汀可降低肝癌发生率、卵巢癌复发率和乳腺癌死亡风险。而此前的研究已经显示乳腺癌患者及一种乳腺癌亚型——炎性乳腺癌患者可从他汀类药物治疗中获益。

越来越多的研究表明，他汀类药物不仅仅能降脂，还能防治多种癌症。但专家警告说迄今为止还没有明确的铁证——研究往往限定在临床前实验室分析，以及对大量患者的回顾性分析中得出的。“只要接触过基础的统计学课程的人都知道，如果你进行了100次试验，那么总能在其中的5项试验中发现你想要的结果，而这仅仅是出于概率，” Georgetown大学 Lombardi 综合肿瘤中心的Louis Weiner博士说。

换句话说，他告诉MedPage Today，“你看到的二者之间的联系越多，你就越可能发现貌似重要的结论，但事实上它们并不重要。这并不意味着他汀可以起到重要的作用，” Weiner说道。这些关联或许是真实的，但“我们面前的挑战是确定前瞻性试验中的临床介入，一种明确的临床措施才能帮助我们厘清他汀使用是否确实能够改善癌症患者的转归。”

尽管他汀在防治癌症方面明显获益已经报道，美国德克萨斯大学MD 安德森癌症中心Naoto Ueno 指出，他汀和癌症之间的关系还存在许多疑问。例如，目前有两种类型的他汀，即亲脂性他汀和亲水性他汀。既往的大多数研究并未区分这两种类型他汀。两种类型他汀的特征并不一样，也许对癌症患者预后的影响也存在差异。此外，目前也不能确定能发挥癌症防治作用的他汀剂量，且尚无生物标志物可用来选择获益的患者群或评估他汀的疗效。他说，对于他汀而言，现在已经到了讨论2期随机试验的时候，但还不到展望3期试验的时候。

其他不同的论点

美国Helen F. Graham 癌症研究中心Bruce Boman 表示，现在是开展临床研究的时候了。他透露，他正在牵头开展一项随机、安慰剂对照研究——NSABP P-5 研究。该研究旨在评估瑞舒伐他汀（10 mg/d，治疗5 年）对可切除Ⅰ~ Ⅱ期结肠癌患者复发风险的影响，Boman 告诉MedPage Today，现在已经到了对临床试验进行割裂分析的时候，因为探讨癌症和他汀类药物的观察性研究正变得越来越多。这些研究吸引人的注意，并为醒目的标题带来素材，但不应该作为医学决策的依据。

Boman说，很多时候研究者所作的是应用出于另一目的收集到的数据并从全新的角度做出阐释。它有时候给人启迪，有时候又带来矛盾的信息。举个例子，Boman说，旨在探索癌症与他汀类药物的观察性研究往往带来混杂的结果。当有一篇研究显示他汀有获益的时候，往往同时出现许多篇得出相反结论的文献。

NSABP P-5试验可以解决上述问题。Boman说计划纳在500个医疗点入1700 例患者，目前已纳入300 例。受试者将随机每天使用安慰剂或10 mg罗苏伐他汀，持续治疗5年，研究者将观察疾病的复发率有无效应。因为癌症是一种长时间积累的疾病，试验也处于其早期，因此还需要几年的时候才能得出结果。同时，我们也在渴望着出现更多的类似AACR会议上的研究。

美国约翰霍普金斯大学TeemuMurtola 报告的研究入选31 236 例新确诊的乳腺癌患者，中位随访3.2年。结果发现，乳腺癌患者确诊后应用他汀有明显的生存获益：局限性和转移性乳腺癌患者的乳腺癌死亡风险分别降低67% 和48%。美国Roswell Park 癌症研究所Michelle Amsler 报告了一项有关卵巢癌的分析。该分析纳入60 例确诊卵巢癌的糖尿病患者。尽管样本量较小，但研究者仍然发现，服用他汀的患者卵巢癌复发风险较未服用他汀者降低83%。

第三项研究由美国国家癌症研究所Katherine McGlynn 报告。研究者对比了他汀在75 例肝癌患者和373例对照受试者中的作用。单因素分析表明，应用他汀可促使肝癌风险降低40%。校正肝炎病毒感染、肥胖、糖尿病和肝硬化等因素后，他汀仍可促使肝癌风险降低52%，但无显著统计学意义。

美国费城Fox Chase癌症中心的Nestor Esnaola博士评论道，这些研究良莠不齐，有些仅仅是泛泛而谈，而有些则有详细描述。而且他们对临床前证据进行了严谨筛选“在某些临床情境下，研究显示在分子水平可对癌症产生影响，”他这样告诉MedPage Today。但临床前数据和回顾性研究无论做得如何精彩，其结论仍然只是“建议性的”。如果出现真实的信号，那么临床试验可以帮助我们做出决定。

与他汀相关的拓展阅读：

• FDA批准阿托伐他汀/依折麦布复方片剂上市
• Eur Heart J：他汀可延缓高危冠脉疾病患者疾病进展
• Neurology：卒中前使用他汀类药物减轻缺血性卒中的临床症状
• AACR2013：他汀类药物可显著降低乳腺癌死亡率
• MedPage：加拿大新指南称糖尿病患者40岁时应该使用他汀类药物
• JACC：高剂量他汀治疗存在两难抉择
更多信息请点击：有关他汀更多资讯

Jury Still Out on Statins in Cancer
WASHINGTON – Can statins, the widely used cholesterol-lowering drugs, play a role in cancer treatment?
Three studies presented here this week at the annual meeting of the American Association for Cancer Research suggest – at a casual glance – that the answer is Yes.
Researchers reported that statin use was associated with reduced risk of recurrence in ovarian cancer, with lower incidence of liver cancer, and with reduced mortality in breast cancer.
Earlier research has also suggested benefits in breast cancer and in patients with a subtype of the disease, inflammatory breast cancer.
Although that sounds as if the evidence for statins is mounting, experts caution that there's so far no proof – research is pretty much confined to preclinical lab analyses and retrospective looks at datasets of varying numbers of patients.
"Anyone who's ever taken a basic statistics course knows that if you do 100 experiments, five of them will give you the results you're looking for just by chance," said Louis Weiner, MD, of Lombardi Comprehensive Cancer Center at Georgetown University.
In other words, he told MedPage Today, "the more associations you look at the more likely you are to find something that looks important -- but isn't."
"That doesn't mean that's what's going on here with the statins," Weiner said. The associations may be real, but "the challenge before us now is to design clinical interventions prospectively that will in a very defined way help us understand whether the use of statins can actually improve the outcomes in people with cancer."
Despite the apparent benefits reported here, there are many questions about statins and cancer that need answers, said Naoto Ueno, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who led the earlier study in inflammatory breast cancer.
For instance, he told MedPage Today, there are two types of statins – the lipophilic and the hydrophilic drugs. Most previous research doesn't distinguish between them and their characteristics might make a difference in outcomes.
It's also not clear if the dose needed for an effect in cancer is the same as that needed to lower cholesterol. And no one knows what biomarkers might be useful to select patients or to measure the effect, Ueno said.
Statins are "ready for prime time if you're talking about phase II randomized trials," he said, "but not for phase III studies."
Others differ on that point.
Bruce Boman, MD, PhD, of Christiana Care's Helen F. Graham Cancer Center in Newark, Del., is leading a randomized placebo-controlled study, under the aegis of the National Surgical Adjuvant Breast and Bowel Project (NSABP), that will look at the effect on recurrence of statins in patients with resected stage I or II colon cancer.
It's time to get cracking on clinical trials, Boman told MedPage Today, because of the growing number of observational studies looking at statins and cancer. That research piques interest and draws headlines, but shouldn't be the basis for medical decisions, he said.
Very often, Boman said, what investigators are doing is using data collected for another purpose and looking at it from a new angle. That can be revealing, but it can also be confusing.
For instance, Boman said, the observational studies looking at statins and cancer have had mixed results. "There are as many studies out there that don't show benefit as ones that do," he said.
The NSABP P-5 trial may help clarify the issue.
Boman said it has already enrolled 300 patients, of a planned 1,700 at 500 sites. They'll take a placebo or 10 mg of rosuvastatin (Crestor) every day for 5 years and investigators will see if there's any effect on recurrence of the disease.
Because cancer is a disease that takes time to develop and the trial is in its early stages, it will be several years before there's an answer. In the meantime, look for more studies like these presented at AACR:
Researchers led by Teemu Murtola, MD, PhD, of Johns Hopkins Bloomberg School of Public Health looked at records of all 31,236 newly diagnosed breast cancer patients in Finland from 1995 to 2003. After a median follow-up of 3.2 years, they found that post-diagnostic statin use was associated with a 67% reduction in the risk of breast cancer mortality for women with localized tumors and a 48% decrease for women with metastatic disease.
An analysis guided by Michelle Amsler, PharmD, of Roswell Park Cancer Institute in Buffalo, N.Y., looked at records of 60 diabetic women diagnosed with ovarian cancer between 2003 and 2010. In what Amlser called "a relatively small population," they nevertheless saw an 83% reduction in the risk of recurrence among women taking a statin, compared with those who were not.
Investigators led by Katherine McGlynn, PhD, of the National Cancer Institute in Bethesda, Md., used data from a large health maintenance organization to compare 75 liver cancer patients with 373 matched controls. In a univariate analysis, statin use was associated with a statistically significant 40% reduction in the risk of liver cancer. The finding "remained consistent" at a 52% reduction – but was no longer significant – after adjustment for such things as hepatitis infection, obesity, diabetes, and cirrhosis.
The studies range from the "small and modest" to the rather more elaborate, commented Nestor Esnaola, MD, of Fox Chase Cancer Center in Philadelphia.
And they mesh well with preclinical evidence that "in some settings (has shown) an impact on cancer at the molecular level," he told MedPage Today.
But preclinical data and retrospective studies – no matter how compelling and well-done – are only "suggestive," he said.
"Clinical trials will help us decide if this is a real signal."