我父亲肺鳞癌的治疗贴(2014年3月1日驾鹤西去）

老马 · 发表于 2012-12-9 17:19:26

Could Less be More? Low-Dose Chemotherapy Goes on Trial
Ken Garber
Judah Folkman, M.D., is accustomed to skeptics. When he first proposed, 30 years ago, the existence of a protein in the blood that blocked tumor blood vessel growth, the idea was almost universally ridiculed. Antiangiogenesis, of course, is now mainstream.

In April 2000, Folkman offered a new heresy: continuous, low-dose chemotherapy that, by targeting the endothelial cells that form the tumor’s blood supply, might work against drug-resistant tumors.

“We said that, in some patients, you may be able to rescue them by changing the schedule and doing antiangiogenic chemotherapy,” said Folkman. The idea, also dubbed “low-dose” or “metronomic” chemotherapy, challenged the long-entrenched “more is better” orthodoxy, and many oncologists openly scoffed.

Now Folkman’s idea is being put to the test. Three North American clinical trials of metronomic chemotherapy are under way. Each uses low-dose, continuous chemotherapy in combination with commercially available antiangiogenesis drugs.

“The animal experiments are promising, the concept is plausible, and well designed clinical trials should be used to evaluate it,” said Ian Tannock, M.D., Ph.D., professor of medical oncology at the University of Toronto. Tannock leads one of the trials, using low-dose cyclophosphamide and Celebrex (celecoxib) to treat metastatic renal cancer. But, Tannock cautioned, “There’s certainly no basis for using it outside the setting of a clinical trial.”

In this trial, patients receive a daily 50mg/m2 oral dose of cyclophosphamide indefinitely until the cancer progresses or toxicities emerge. By comparison, Tannock noted that a typical standard regimen would include cyclophosphamide doses of 500 to 1000 mg/m2 intravenously every 3 weeks.

Low-dose/antiangiogenic/metronomic chemotherapy has precedents. “Using low-dose chemotherapy is not a new idea,” said Robert Kerbel, Ph.D., of the University of Toronto. “In fact, there are oncologists who will say to you, ‘Hell, we’ve been using low-dose chemotherapy, or some kind of continuous regimen . . . for years.’ ” Anecdotal reports of responses to low-dose palliative chemotherapy are common. In childhood leukemia, continuous “consolidation therapy” lasting 3 years is now standard.

“Eighty-two percent of the last 400 kids I’ve taken care of with leukemia are alive and well, and 89% are alive at 11 years, and it’s all metronomic,” said pediatric oncologist Barton Kamen, M.D., Ph.D., of the Cancer Institute of New Jersey, Princeton. “Did I win because I was killing the vasculature in the bone marrow? I can’t tell you that. But I can tell you that the use of chronic, repetitive low-dose medicine, regardless of the target, works—absolutely works.”

Others are skeptical. “Gee, it sounds wonderful, but there [are a lot] of good theories out there,” said Roy Baynes, M.D., Ph.D., director of the bone marrow transplant program at Wayne State University in Detroit. “I would just make a plea, before everyone jumps overboard—let’s get the data.”

The antiangiogenic chemotherapy theory originated in the early 1990s with Tim Browder, M.D., an oncology fellow in Folkman’s laboratory. Browder and Folkman were puzzled that chemotherapy, which was known to have antiangiogenic effects, always led to resistance. Tumor endothelial cells, in theory, should not become resistant to chemotherapy because they lacked the tumor’s genetic instability. Why, then, didn’t chemotherapy work better?

“I had this discussion many times with Browder,” Folkman recalled. “Browder came back and said, ‘I think the reason that chemotherapy doesn’t act all the time on endothelial cells is they keep stopping [treatment]—taking vacations, treatment vacations.’” Browder reasoned that giving chemotherapy continuously would prevent endothelial cell recovery and effectively starve tumors of their blood supply.

Proving the theory took years of exhaustive laboratory work, culminating in Browder and Folkman’s April 2000 paper in Cancer Research. Working in mice, Browder showed that continuous low-dose cyclophosphamide could cure otherwise invariably fatal tumors. After creating a super-resistant tumor line, Browder then showed that low-dose cyclophosphamide could greatly slow tumor growth and improve survival.

The drug’s antiangiogenic effects, a variety of careful assays demonstrated, were responsible. “The tumor would be drug resistant ... but the endothelial cell would not,” said Folkman. “And you could get [disease] control.”

Kerbel, at the same time, published results showing that a combination of low-dose vinblastine and an anti-VEGF (vascular endothelial growth factor) receptor antibody could completely eradicate tumors in mice. “The tumors completely regressed,” Kerbel recalled. “They never came back during 7 months of continuous therapy.” This and Browder and Folkman’s work together laid the theoretical groundwork for today’s clinical trials.

Besides Tannock’s renal cancer trial, two other human trials are under way. Rena Buckstein, M.D., of the Toronto Sunnybrook Regional Cancer Center, is leading a multicenter trial also using low-dose cyclophosphamide with celecoxib to treat non-Hodgkin’s lymphoma.

Meanwhile, oncologists at the Dana Farber Cancer Institute, Boston, are undertaking separate pediatric and adult trials using a combination of two chemotherapy agents—low-dose cyclophosphamide and etoposide—and two antiangiogenic drugs, celecoxib and thalidomide.

“I think this has immense promise, and it deserves to be tested,” said principal investigator Mark Kieran, M.D., Ph.D. “If the philosophy is right, we will at least see a little bit of activity.”

Kerbel said he is worried that, because celecoxib and thalidomide are not the optimal antiangiogenic agents, these trials will not demonstrate metronomic therapy’s true potential. Experimental drugs targeting VEGF or the VEGF receptor would theoretically be more potent, but drug companies will only test such drugs against standard-dose chemotherapy, to advance their chances of Food and Drug Administration approval. “It’s a bit frustrating,” said Kerbel, who added that he hopes that the early trials will show enough effect to convince drug companies to test their new agents with low-dose chemotherapy.

Although results in mice and anecdotal reports in humans seem to favor the metronomic idea, there is at least one big worry: resistance. While antiangiogenesis, in theory, bypasses the genetic instability that leads to tumor resistance, in some of Browder and Folkman’s experiments the tumors eventually returned.

“Even if you target the vasculature, there may be ways that you still nevertheless get resistance,” said Kerbel. For example, tumors may evolve to survive in relatively hypoxic conditions. Or, in response to stress, they may secrete cytokines or growth factors that promote angiogenesis.

“A tumor could escape an angiogenesis inhibitor,” admitted Folkman, who, nevertheless, is not worried. “We’ve actually seen that, but it turns out that now you just give more angiogenesis inhibitor, and you override it.”

Some think that metronomic chemotherapy not only blocks angiogenesis but also directly targets tumors. “I believe that metronomics is working whether the vasculature really turns out to be the target or not,” said Kamen. The anti-inflammatory effects of low-dose chemotherapy may, Kamen speculated, allow natural killer cells better access to tumors. And since many chemotherapy drugs only work against dividing cells in the process of synthesizing new DNA—the so-called “S phase”—continuous chemotherapy is necessary to kill all tumor cells present, in Kamen’s view. Higher doses, if given intermittently, will not help. “You can’t kill a cell twice,” said Kamen. “That’s what it comes down to.”

Skeptics counter that high doses are absolutely necessary to eradicate tumors. “Systematic undertreatment compromises outcome,” Wayne State’s Baynes said.

So the fate of metronomic chemotherapy rests on the clinical trials. Even if they succeed, it will not be easy to convince oncologists to abandon the “maximum tolerated dose” philosophy.

“There’s this view: If you’re not vomiting and you’re not having your hair fall out, then there’s probably nothing happening to your tumor,” said Kerbel. “That’s a very entrenched view among oncologists. Since that’s been a prevailing way of doing things for decades, it’s not easy, based on a couple of early clinical trials, to turn that around.”

Folkman is more optimistic, since many doctors have already used low-dose chemotherapy successfully without knowing why it works. “Clinicians come up all the time and say, ‘I want to tell you a secret. I never stop chemotherapy,’” Folkman said. “‘I keep giving it, but I was afraid to mention it, because everyone thought I was giving homeopathic doses.’” Now, Folkman said, “They have an explanation.” All that’s missing is the proof.

seacat · 发表于 2012-12-9 22:35:32

本帖最后由 seacat 于 2012-12-9 22:37 编辑

低剂量CTX还是很安全的，我看过病例，最长连续使用65个月。每天50mg口服，工作生活如常。
实际上我们不需要连续使用这么长时间，1、2个月就行了。

阳光灿烂的日子 · 发表于 2012-12-11 16:49:21

英雄武松发表于 2012-12-1 20:07
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我妈每天上午一盒舒化奶。舒化奶不坏肚子，其他的奶制品吃了坏肚子。, u; E. M& D6 u) U3 s* E
从明天起，就买乳铁蛋白舒化奶了。

哪里有卖乳铁蛋白舒化奶

老马 · 发表于 2012-12-11 19:36:08

本帖最后由老马于 2012-12-12 23:19 编辑

2012-12-11，去省人民医院检查胸腹部B超，还有血常规，T淋巴亚组细胞、肝、肾功能、肿瘤指标，以及抽血做生物治疗。
胸腹部B超结果：无胸水、肝，肾、肾上腺、胃、前列腺无异常。
血常规：白细胞6200，血小板28万，血红蛋白10.5克。
肿瘤指标：cea 5.4，ca125 64.6 cy211 7，C反应蛋白18（应该是炎症的原因）
肝功能正常，肾功能中尿素8.40，略超（正常上限是7.14)。
T淋巴亚组细胞数据比上次有改善。

蜜小青的爸爸 · 发表于 2012-12-13 15:02:04

老马发表于 2012-12-7 12:21
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有胸水不适合放疗。; M3 S( o/ ]4 p# D
骗吃2992，难度比较大，因为2992很容易腹泻。
& s& Z; M1 ~" x; m特无效，联184也难的。

我爸爸吃了特后，皮肤好干燥，直到现在挺特十来天了，皮屑还是好严重，我怀疑特真的无效么，我看你爸爸也是吃特皮屑很多啊。好想等稳定了再吃特，可是又不敢贸然的试。还是想试试2992.放疗我也渐渐的在考虑了，等胸水控制住了，身体状况好了，就放疗看看。真害怕放射性肺炎。

lichbug · 发表于 2012-12-15 20:52:06

老马发表于 2012-12-9 17:19
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$ r( H5 W, c3 Z4 {+ BCould Less be More? Low-Dose Chemotherapy Goes on Trial6 o8 D+ D' E N& G% N0 x' w
Ken Garber! ], u9 d2 L) L; }* p/ d
Judah Folkman, M.D., is accusto ...

老马你好，看到你父亲情况不错，真心恭喜！
我父亲属07年得病，化疗6次服易，11年怀疑脑膜转移全脑放4000，12年5月肺部进展停易开始力比泰+顺铂，化疗6次后医生建议单药2次，现在已经8次化疗了，父亲身体尚可，但是心里不愿意再化疗了，我也咨询了大夫，他觉得我们应该继续维持单药。大夫分析我父亲是T790M突变，我认为是不是现在停药7个月已经可以重新再上易试试了？单药小剂量化疗和易瑞沙+力比泰间隔使用哪个效果更好？另外父亲这两天突然头疼，强度比去年脑转时小，去年全脑放完有大夫拿父亲的片子就不认为是脑转，今年又疼，周一MRI，如果真是脑部复发，请问还有什么好方法？http://www.yuaigongwu.com/thread-6970-1-2.html这是病情记录，多谢指导。

感受生活 · 发表于 2012-12-17 09:22:26

本帖最后由感受生活于 2012-12-17 10:09 编辑

老马：有急问题向您请教：
最近非常纠结于妈妈的下一下治疗情况，想请教一下您：
妈妈（肺腺四期）自2010年查出来后，使用一次多西他赛，效果不好，然后使用两次培美化疗效果很好，后来就一直替换服药易、特、2992等，从没有大幅度降过指标，2年半期间CEA指标一直是缓慢增长，到今年6月份是37。想到两年之前培美的效果较好，就又进行了两个周期的培美化疗，但效果并不是很理想，第2次化疗后20天查CEA为32.4。
接着我们服用2992，80MG每天，一月后即9月15日，CEA降为26.74。
继续服2992相同剂量至10月13日，复查时CEA却上升到了34.49。
因易已有10个月未服了，就服了一个月的300毫克的易瑞沙，11月15日的CEA 翻倍上升为66 。
更换药物为每天150MG的特罗凯，服用一个月，今天12月15日CEA：93.7，再次大幅度增长。
最近一周，妈妈突然大腿根处疼痛严重，以至于不能走路。热敷后逐渐减轻。
但从前天开始，妈妈感觉腰痛，两天来逐渐加重，怀疑是否骨转。今年6月作过骨扫描，没什么情况，这么快就转了？
请教老马，我估计可能是骨转，需要化疗了，请老马帮忙看看什么治疗方案合适？
请别介意，因为现在大脑空白了，所以请教了几个版主，只为多汇总经验，下午就要找医生提前定个床位了，很难的，请老马指教，对不起。

老马 · 发表于 2012-12-17 10:27:41

先确定是否骨转，骨转就打骨转针。
化疗仍可以用培美单药，或者联用阿瓦斯汀。
后面靶向药可以考虑2992联用Xl184。

感受生活 · 发表于 2012-12-17 16:25:27

老马发表于 2012-12-17 10:27
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0 {. v, k9 [ k( i# V先确定是否骨转，骨转就打骨转针。
! d( F; h5 c8 X) g h化疗仍可以用培美单药，或者联用阿瓦斯汀。5 p- v( ^/ n+ M7 S4 F3 F& o
后面靶向药可以考虑2992联 ...

万分感谢老马!下午去找医生开了骨扫描了。

棒海狸 · 发表于 2012-12-17 22:03:21

本帖最后由棒海狸于 2012-12-17 22:08 编辑

马老师，今天看了你写的免疫组化表达的意义这篇文章，还要细细体会，。想请教你，我父亲的免疫组化结果:
c-met(弱+)，Tubulin-B(+),TS(-)是代表什么意思啊？问过好多医生，都没结果啊。另一个问题，也是很想弄明白的；就是为我们做手术的医院说肺癌的新分类现在是用百分比，比如腺癌：腺泡型百分之多少，乳头型百分之多少，但就不写分化程度。我父亲是肺浸润性腺癌，腺泡型，很想知道分化程度。马老师你能告诉我吗？