What is Metronomic Chemotherapy?
Metronomic chemotherapy is a relatively new type of chemotherapy that uses low doses of oral (pulse) chemotherapy given on a continuous treatment schedule. Since it is given daily or every other day, the chemotherapy is given at lower doses then typical chemotherapy, often with a reduced toxicity profile. That reduction in toxicity usually results in fewer side effects.
How Is Metronomic Chemotherapy Different than Traditional Chemotherapy?
Conventional chemo is given at high dosages, known as maximum tolerated dose, or MTD. The goal of conventional chemotherapy is to kill rapidly dividing cancer cells. But there are normal cells that also replicate quickly, so it can also temporarily damage them, too. Most commonly, it is the GI tract cells and the white blood cells that are temporarily damaged. To allow these cell populations to recover, we put a break period into the chemotherapy schedule, usually a full week. The typical schedule for MTD is weekly, although some treatment schedules give breaks of up to three weeks.
In contrast, the goal of metronomic chemotherapy is NOT to kill the cancer cells directly. Instead, metronomic chemotherapy targets and inhibits tumor blood vessels growth. Why the blood vessels, instead of the tumors themselves? Because tumor blood vessel cells are more active than normal blood vessel cells, and they bring nutrition to the tumor. Blood vessel growth is technically called angiogenesis, so you will hear metronomic chemotherapy called “anti-angiogenic.”
There is also evidence that some low-dose chemo drugs, like cyclophosphamide, have an effect on tumor immunology: they alter a subset of immune system cells in the T-lymphocyte family (regulatory T-Cells).
When is metronomic chemotherapy used?
We are truly still at an early stage in understanding the mechanisms and the efficacy of this approach. I use this approach for some patients with metastatic disease — such as spread of the tumor to the lungs — in an attempt to slow progression of the metastatic disease. (Traditional chemo does not work well for dogs with metastasis.)
Another use is for dogs that have failed standard of care – meaning their cancer came came back or progressed on the recommended drugs – or if there is no standard of care for an uncommon cancer.
Metronomic chemotherapy has also been used recently for splenic hemangiosarcoma and incompletely removed soft tissue sarcomas.
Although the idea of metronomic chemotherapy is relatively new, there are cancers for which we have used a low-dose oral approach for years. Examples include low grade/small cell lymphomas (especially in cats) with Leukeran and multiple myeloma is dogs with melphalan.
Cyclophosphamide (CYC) is the drug most commonly used in metronomic protocols in people and pets. CYC can be combined with a non-steroidal anti-inflammatory drug (NSAID) such as piroxicam, for its potential ant-cancer effect on certain cancers. Remember, even though NSAIDS are not chemo, they can also cause side effects (GI, liver, kidney), so discuss with your oncologist or vet if it is appropriate to use them in your dog.
Another chemo drug that can be given continuously at low doses is chlorambucil (Leukeran), and more recently Lomustine.
CYC can also be combined with some of the new targeted chemo drugs, such as the receptor tyrosine kinase inhibitors. In fact my preferred metronomic approach combines Palladia with low dose CYC.
Palladia a relatively new oral mast cell tumor (MCT) drug with anti-angiogenic and anti-proliferative effects for other tumors as well. The most common are GI side effects, and most are mild to moderate in intensity. In my opinion, most Palladia side effects are manageable with early recognition, and early recognition is critical. That means I adjust or temporarily stop the Palladia if needed. Side effects include diarrhea, vomiting, lethargy, GI ulcers, and weight loss. That’s why I monitor my patients carefully with physical examinations, monitoring weight closely, and blood work.
How frequent are visits?
Personally, when I start these protocols I re-check every two weeks for four to six weeks. After that, I start re-checking every four to six weeks, depending on the case. At these visits, I am doing my exam, comparing weight, running some basic blood work, and periodically checking tumor response (which often requires chest X-rays or ultrasound, depending, again on the case). If we are having side effects, I may adjust the dose adjustments and/or take a treatment break.
How quickly can I expect to see results? How long will my pet be on a metronomic protocol?
Since we are targeting the tumor blood vessels, responses can take weeks. I recommend at least six to eight weeks to see an effect. Remember in a tumor that failed other therapies, stabilizing the disease (meaning it doesn’t progress) can still be considered a success.
I typically recommend metronomic chemo be given for at least six months, if effective.
What are the side effects?
In general metronomic protocols are well-tolerated, and most side effects are mild (mild decreased appetite, vomiting, diarrhea).
Although uncommon, CYC can cause an inflammation to the bladder, called sterile hemorrhaging cystitis. The symptoms are similar to a UTI (urinary tract infection) – increased straining, peeing small amounts more frequently, sometimes bloody. In these cases, CYC should be discontinued.
If any of the side effects are severe, I tell my clients to stop the chemo, give prescribed nausea/vomiting and/or diarrhea medications, and contact my nurses.