Metronomic Timing Adds Antiangiogenic Punch

Continuous use of low-dose antiangiogenic agents may be the key to making cancer a manageable, chronic disease, say researchers investigating the approach. Such a schedule, called “metronomic,” appears to reduce the risk of recurrence because of the continuous coverage while also decreasing toxicity with the lower doses. Clinical trials are now in the planning stage that will add metronomic treatment after a standard cytotoxic regimen in breast cancer. Investigators became aware of the potential of metronomic scheduling when they saw that low doses of conventional cytotoxic agents such as cyclophosphamide and fluorouracil (5-FU), given over long periods, inhibited vascular endothelial cells as well as tumor cells. In animal models this caused regression of difficult tumors such as Lewis lung carcinoma, EMT-6 breast carcinoma, and L1210 leukemias in animals. The metronomic concept suggests that current chemotherapy schedules may not be taking full advantage of a standard agent's ability to attack blood-vessel formation in tumors. Angiogenesis pioneer Judah Folkman, MD, Professor of Pediatric Surgery and Cell Biology at Children's Hospital of Harvard Medical School in Boston, and other researchers are considering the possibility that current dosing schedules do not optimize conventional chemotherapy agents. “Many standard chemotherapy agents have powerful antiangiogenic activity besides their cytotoxicity,” Dr. Folkman said in an interview at the recent Chemotherapy Foundation Symposium in New York City. He noted that drugs such as docetaxel, paclitaxel, mitoxantrone, and cyclophosphamide are powerful antiangiogenic agents. If a drug does have “dual” action, then tumor resistance to that drug would not preclude an antiangiogenic effect on the tumor during prolonged administration. “It is possible that continuation of chemotherapy may have antiangiogenic benefits even if the drug's cytotoxic benefits have waned,” Dr. Folkman said. “When you run out of options, maybe you haven't really run out of options.” Whn a metronomic schedule is directed at endothelial cells, they will not become drug resistant like tumor cells, because endothelial cells do not have a mutating system. Larry Norton, MD, Head of the Division of Solid Tumor Oncology and the Morma S. Sarofim Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center in New York City, said he is advising researchers to consider metronomic dosing in new treatment regimens. “If you don't ignore the endothelial cells, you begin to see options you did not have before,” Dr. Norton said in his presentation on breast cancer at the Symposium. “For 50 years we have treated only tumor cells, but the endothelial cell also exerts enormous control. To kill the vasculature that supplies the tumor with blood, a schedule has to give the drugs frequently, and dose isn't as important as the frequency of administration.” He said a new breast cancer regimen under consideration alternates low-dose paclitaxel with low-dose docetaxel (Taxotere) for 18 cycles, following the standard FEC (5-FU, epirubicin, and cyclophosphamide) regimen. “This might be a very good antivascular regimen, because it exposes the blood vessels to a taxane almost continuously,” Dr. Norton said. “And because it exposes the nerves to paclitaxel every two weeks, and exposes other tissues to Taxotere every two weeks, the toxicity to those tissues may be minimal. Trials are needed to find out if what we are doing [with standard chemotherapy] is really giving antivascular therapy while we think we are giving anticancer cell therapy.” Pediatric Populations Pediatric oncologists have been using timed, sequential dosing at constant intervals for years in leukemia patients, says Barton Kamen, MD, Professor of Pediatrics at the Cancer Institute of New Jersey in New Brunswick, even though they didn't call it metronomic. “The principle of metronomics is that there is a dose of medicine which will allow continuous therapy with minimum rest, at a dose well below our typical maximally tolerated dose which limits toxicity,” Dr. Kamen said. In a presentation on metronomic therapy at the most recent American Association for Cancer Research Annual Meeting, Dr. Kamen noted that metronomics is really not a new process, citing papers from the 1980s that called for selectivity in chemotherapy. “Selectivity is the key,” he said. “Drowning a patient and a tumor with an LD10,000 is not going to kill much more than an LD100 appropriately applied. We need to look for subtle differences and find a dose of medicine that works, and use it for extended times rather than short high doses.” Resistance during Rest To balance toxicity with efficacy, a conventional chemotherapy regimen will schedule episodic dosing of a cytotoxic drug at or near the maximally tolerated dose (MTD), followed by periods of rest to allow normal tissues to recover. But these rest periods allow tumor cells to mutate and become drug resistant, notes Robert S. Kerbel, PhD, Head of the Department of Molecular and Cellular Biology Research at Sunnybrook and Women's College Health Sciences Center in Toronto, as he wrote in an article in Carcinogenesis (“Tumor Angiogenesis: Past, Present and the Near Future, Carcinogenesis 2000;21[3]:505–515). Dr. Kerbel said he believes that drug resistance can be largely traced to instability of the tumor cell genome, and to the resultant ability of tumor cell populations to generate phenotypic variants rapidly. “Anti-cancer strategies should be directed at eliminating those genetically stable, normal diploid cells that are required for the progressive growth of tumors, namely the endothelial cells which supply the tumor,” he wrote. Specificity for tumor-associated vasculature by anti-cancer agents is achieved by virtue of the fact that many of the endothelial cells that make up these blood vessels are in an immature, cycling, and “activated” state, in contrast to the endothelial cells associated with normal tissue and organ blood vessels. Other researchers have found that some conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells, contributing to the antitumor efficacy of chemotherapy and delaying or preventing the acquisition of drug-resistance by cancer cells. Giannoula Klement, MD, a postdoctoral fellow at that institution, found that metronomic dosing could be especially effective if angiogenesis-inhibiting drugs are added to the chemotherapy mix (Klement G, et al: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105[8]: R15-R24). But investigators also note that there are no reliable surrogate markers available yet to monitor the effects of antiangiogenic drugs when they do not cause tumor regressions. There is also concern that a metronomic schedule with chronic use of angiogenesis inhibitors may lead to delayed toxic side effects in humans. Fundamental Change in Thinking Douglas Hanahan, PhD, Professor of Biochemistry and Biophysics at the Hormone Research Institute of the University of California San Francisco, believes that selecting an optimum antiangiogenic dose that is nontoxic yet efficacious may be difficult without surrogate markers. A strategy that deemphasizes the tumor cell as a target requires a fundamental change in thinking, Dr. Hanahan said (Hanahan D, et al: Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105[8]:1045–1047). But Dr. Hanahan says such a strategy could potentially include re-treatment of refractory cancers with agents that have previously failed, or the use of agents traditionally deemed inactive or ineffective in a particular cancer type. Subscriptions to OT If you are an oncologist or an oncology nurse, you should already be receiving a subscription to OT. If not, quality for a complimentary monthly subscription by contacting Deborah Holmes via e-mail at [email protected] or by fax to 212-886-1209. If you are not an oncologist or oncology nurse and are interested in subscribing, contact Lippincott Williams & Wilkins, 16522 Hunters Green Parkway, Hagerstown, MD 21740; 800-638-3030; in Maryland, call collect 301-824-7300.

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