Metronomic Chemotherapy

What if cancer could be treated by chemotherapy that was easier, cheaper, and more effective than current therapies—and had fewer side effects? People and their dogs can look forward to more comfortable cancer therapy if a new study in progress at Colorado State University succeeds.

Barbara Biller, DVM, PhD, an assistant professor of Oncology at CSU, recently tested a relatively new cancer treatment technique called metronomic chemotherapy. The study was funded in part by the AKC Canine Health Foundation (CHF). Dr. Biller explained her research at CHF Breeder’s Symposium in Fort Collins, CO.

Why dogs? Humans and dogs share many of the same kinds of cancer. Their tumors are identical in location, growth, and even genes. And just as dogs live shorter lives than people, their disease cycles are shorter, meaning it takes less time to study a number of patients. Most studies in the past used laboratory mice. Cancer was given to special mice with impaired immune systems. Dogs, like people, have naturally occurring cancer. Canine cancer is an excellent model for studying human disease.

Chemotherapy works by killing cancer cells because they grow faster than other cells. Current medications target these fast-growing cells. Patients are given the maximum tolerated dose (MTD), usually by intravenous infusion, then wait several weeks before another treatment so normal cells can recover from the toxin. Unfortunately, some other normal body cells also grow fast:  Bone marrow cells, intestinal cells, and hair follicle cells. This causes the well-known side effects of chemotherapy, including a drop in red blood cell count, nausea, and hair loss.

Dogs less frequently have severe reactions to chemotherapy than people do, but a lower-cost oral administration technique would benefit dogs and their owners.

“All options in veterinary oncology hinge on quality of life, not quantity,” Dr. Biller emphasized.

In contrast to the large doses of toxic chemicals used in classic chemotherapy protocols, metronomic chemotherapy relies on smaller, more frequent doses, often of the same proven medicines. Think of the tick, tick, tick of a metronome. Treatment usually is given in a daily oral dose, reducing costs and hospital visits.

Though it uses the same chemicals as MTD chemo, metronomic chemo works differently. Rapidly growing cancer cells need a blood supply. The tumor secretes substances that stimulate blood vessel growth. Used metronomically, the commonly used cancer drugs work not on killing the tumor, but on killing endothelial cells that line the blood vessels. There is no effect on normal cells typically damaged by chemotherapy.

With a doctoral degree in immunology, Dr. Biller’s special interest is in how chemotherapy reacts with the immune system. She hopes to treat cancer better by integrating chemotherapy with techniques that also treat the immune system. Metronomic chemo appears to have a special ability to “wake up” the immune system, she said.

Some key cells of the immune system do appear to be stimulated by metronomic chemotherapy. Metronomic use of the common chemotherapy drug cyclophosphamide, also known as Cytoxan, selectively kills regulatory T cells (Treg), instrumental in “hiding” cancer from the immune system, without harming other immune system cells.

Perhaps most encouraging of all, patients who no longer respond to standard chemotherapy, both canine and human, seem to respond to metronomic use of the drugs. Oncologists now may have one more important weapon in the arsenal against advanced cancer.

Metronomic treatment is so new in veterinary medicine that there are only four published studies on the topic, Dr. Biller said. She explained that there is no standard yet for which drugs and doses will prove best. In one, a study of human breast cancer patients where MTD doses of Cytoxan failed, 32 per cent of the patients responded to Cytoxan given metronomically. All were treated as outpatients and suffered no side effects. The cost was less than $50 a month.

Dr. Biller’s team conducted a pilot study, giving Cytoxan in metronomic doses to seven dogs with various types of cancer. Over a month, there was no change in the Treg levels, but there were no adverse effects.

For a larger study, the researchers chose dogs with soft tissue sarcoma. The cancer is common in older dogs, usually occurs on the dogs’ legs where it is hard to remove completely by surgery, and it usually grows slowly and doesn’t spread to other spots in the body. By dividing the test group into two groups and administering two different doses of metronomic Cytoxan over 28 days, they found that the higher dose decreased circulating Treg cells and decreased small blood vessels in tumor biopsy samples—two goals of the study. It did not reduce circulating endothelial cells that can migrate to blood vessels and encourage growth. None of the dogs got sick.

This is the first veterinary research to study what doses of drugs should be used in a metronomic way. Dr. Biller envisions it as a starting point for other studies. She predicts that there will be similar studies for other tumor types and drug combinations, or combinations of metronomic and MTD chemotherapy. It’s a starting point with an exciting future for effective, inexpensive, and less toxic cancer treatment.