There are two main problems when it comes to bombarding tumours with chemicals and radiation: it leads to toxic side effects which are sometimes severe, and cancer cells usually develop resistance to treatment, sometimes rather quickly. To help make inroads in solving these problems, Dr. Bob Kerbel and his colleagues are investigating a new type of chemotherapy that targets blood vessels in tumours rather than tumour cells directly.

Newly arising tumours can only grow to less than a cubic millimetre – about the size of the metal ball on a ball-point pen. For these specks to grow into lumps, the cancer cells in the tumour need blood vessels to provide oxygen necessary for energy metabolism and to remove the waste products of metabolism. Because these critical products can only diffuse across four or five cell diameters, tumours need a complex network of vessels to feed all parts of a rapidly growing tumour. This network, known as a vasculature, grows through a process called angiogenesis.

Several new biological drugs have recently been developed and approved for use in humans which inhibit tumour angiogenesis without significantly affecting normal blood vessels elsewhere. Ironically, some existing chemotherapy drugs have also been shown to impede angiogenesis, but the way they are usually administered negates this potential benefit, and also causes severe side effects that in rare cases can be fatal.

In current practice, doctors try to destroy an entire tumour mass. Because they are aiming to kill as many cancer cells as possible, doctors administer cancer-fighting drugs in the largest dose a patient’s body will tolerate. After one of these large “maximum tolerated” doses, the body requires several weeks to fully recuperate from certain side effects before doctors can administer another dose.

But this break period also gives the growing tumour vasculature affected by the chemotherapy sufficient time to recover and tumour growth is often well underway by the time the patient is ready for another maximum tolerated dose.

Kerbel, a senior scientist at the Sunnybrook Research Institute in Toronto, is studying and pioneering an alternative approach to chemotherapy, known as metronomic therapy. “Like the ticks of a metronome, the doses occur at frequent intervals without long interruptions. If small doses are able to arrest angiogenesis, they could be more effective than larger ones over the long-term. The tumour may not be wiped out with a smaller dose, but in some cases it will not be able to grow, spread or even maintain itself for prolonged periods if its blood supply is continually inhibited by a frequent flow of low-dose chemotherapy,” explains Kerbel. Even though the long breaks are eliminated the usual side effects of higher doses of chemotherapy are not increased – in fact they are decreased.

Metronomic therapy is not a simple matter of spreading out the dose of traditional chemotherapy treatments. Researchers must conduct more studies to determine the optimum combination of new antiangiogenic agents and traditional chemotherapy drugs.

One important study by Kerbel, for example, found modest survival benefit of a metronomic course of chemotherapy combined with a new antiangiogenic drug. However, when the two drugs – vinblastine (a traditional chemotherapy drug) and a “molecularly” targeted biologic antiangiogenic agent – were combined, survival improved remarkably with very few toxic side effects, despite a half-year of therapy.

A second, related challenge is to find optimum dosing levels and patterns, known as the optimum biologic dose. By studying the toxicity of a drug, it is relatively easy for scientists to determine the maximum dose that a human body can tolerate. However, scientists like Kerbel don’t want to know how much is too much, they want to know how much is just enough so they can deliver medication as frequently and as long as possible.

In recent research, Kerbel has developed a method to help overcome this hurdle. He and members of his team observed tumour-independent changes in a number of molecular plasma proteins after administering courses of an antiangiogenic agent, which could serve as an indicator of its optimum biologic dose and biologic activity. Similar approaches are being tested to help determine the optimum doses for metronomic chemotherapy.

“Metronomic therapy is a cutting-edge field of cancer research and it could take years to develop clinical applications and implement them, but the potential long-term benefits of this work are significant,” says Dr. Bob Phillips, deputy director of the Ontario Institute for Cancer Research and a career cancer researcher.

Already, researchers in a number of other countries are testing the results of Kerbel’s research in clinical trials. Kerbel has collaborated on some of this research and is helping to plan new trials that will involve breast, colorectal, and prostate cancer patients in Ontario. Some initial phase II clinical trial results in the U.S., Canada and Europe, especially in women with breast or ovarian cancer, look promising. One of these trials involved 70 women with ovarian cancer, 50 of whom were from Ontario and the remainder from the U.S., and was sponsored by the National Cancer Institute in the U.S.

Old drugs, new tricks
In translating their research from the laboratory to the clinic, Kerbel and his colleagues are at an advantage because in most cases, only the drug combinations and dosing patterns are new, while the drugs themselves are already approved. Working with old drugs is less expensive and involves fewer regulatory hurdles than developing new ones.

The laboratory is not the only place where it helps to work with off-patent drugs. In the clinic, the cost of these drugs is a tiny fraction of newly approved pharmaceuticals.

Another major advantage to both taxpayers and patients is that metronomic doses are low enough that they can typically be delivered orally with certain chemotherapeutic drugs. Rather than having to travel to a cancer centre and meet with a health care professional every few weeks to receive a simple injection, chemotherapy patients can take their medications at home on a daily or weekly basis.

Receiving drugs in small, regular doses is also less likely to overwhelm the body than a single massive dose. Kerbel has developed models of highly advanced, widespread metastatic disease in mice using tumours such as breast cancer and melanoma and has shown that certain combinations of two oral chemotherapy drugs given in a low-dose metronomic fashion every day without any breaks for up to five months can have unexpectedly good anti-tumour properties with minimal toxic side effects.

It is for this reason that Kerbel’s work could be so important for some cancer patients. Not only could antiangiogenic metronomic therapy save or prolong lives by destroying devastating tumours; it could also improve the quality of lives by reducing devastating side-effects.