Could Less be More? Low-Dose Chemotherapy Goes on Trial
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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.5 f7 @1 g% K C5 F$ Q/ P. S; d
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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.
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“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. \$ n1 I# H- w( F! y" C
& p3 D4 `5 }/ V. g3 qNow 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.
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“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.”# C" Z. l( U6 @" e A' k4 b8 |3 N
0 k \2 ]3 M' `' N6 P& G: dIn 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.
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" T& O6 m0 A8 Z; tLow-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.2 S) ~ |- Y6 r6 @. K4 s; g
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“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.”* S2 A+ R \$ }4 g4 M6 n, {
4 X7 {0 x) A; \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.”
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8 n! m: R7 e- B( p. cThe 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?
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“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.) X; q7 y4 Z2 T
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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.
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$ j5 k/ O) G: |8 E+ b, ?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.”
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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.
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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.9 @1 i- m+ M, L! a5 }- |+ b5 W
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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.
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“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.”
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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.6 U" n3 d( M/ @2 _; d, o
$ Z' ?" ~! u( r. b. c9 }6 L) M1 bAlthough 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.
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& C, [# D, V* W" z“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." [( {6 x/ f3 `, s! L
2 w1 e6 d4 e( h: I$ K“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.”4 q9 y6 @& O" X0 Z2 z+ H
2 J# v, L! Q O" s/ U1 }, lSome 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.”
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+ u, B$ r5 ?1 cSkeptics counter that high doses are absolutely necessary to eradicate tumors. “Systematic undertreatment compromises outcome,” Wayne State’s Baynes said.
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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.
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0 I/ ?) N4 H4 A+ d' o! b1 Q7 e“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.”( ?% u/ @) J. P& Y% f
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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. |
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