Metronomic Chemotherapy for Dogs

What Happens in Metronomic Chemotherapy

Metronomic chemotherapy is when low doses of chemo drugs are given regularly long term. Metronomic chemotherapy may also be referred to as low-dose continuous chemotherapy or antiangiogenic chemotherapy.²

In metronomic chemo, lower doses that have less toxicity are given more frequently than traditional chemotherapy without an extended drug free interval.¹ For example, traditional chemotherapy may involve a higher dose of drug give once a week for 3 weeks then taking 6 weeks off while metronomic chemotherapy would give a lower dose every other day long term. Often the drug will be given in an oral form so long-term treatment can be given at home by the owner.² Each protocol will vary based on your veterinarian’s recommendation and the type of cancer being treated.

Common Examples of Drugs Used Metronomically

In veterinary medicine the most common metronomic chemotherapy protocols use cyclophosphamide, piroxicam, lomustine, chlorambucil, and more recently toceranib (Palladia).

• Cyclophosphamide, either alone or in conjunction with piroxicam, has been used for treatment of soft tissue sarcomas with incomplete surgical resection along with other cancer types.¹⁸ Cyclophosphamide is somewhat unique in that it is dosed based on the dog’s body surface area (meters squared, or m2) as opposed to by weight. There is great variability among metronomic protocols described for dogs: 7 to 25 mg/m2, once daily to every other day. Daily dosages above 12.5 mg/m2 have both immunomodulatory and anti-angiogenic effects.^2,5,18
• Piroxicam alone is often used daily for the treatment of transitional cell carcinoma in dogs. The dose is generally 0.3 mg/kg daily.¹⁹
• Chlorambucil and lomustine have also been used in canine patients with generally good tolerance for a variety of types of cancer. Dosing is usually 0.2 mg/kg, once daily for chlorambucil and 2.8 mg/m2, once daily for lomustine.¹
• Palladia is a newer treatment the is FDA-approved for treating canine mast cell tumors. The use of tyrosine kinase inhibitors such as Palladia in metronomic chemotherapy shows promising results and may be recommended for a variety of cancers.^6,7

When Metronomic Chemotherapy Is Recommended

Metronomic chemotherapy may be indicated for palliative care or first-line treatment, depending on the cancer type. It can also be used as maintenance therapy after traditional chemotherapy.

First line treatment may be recommended for patients diagnosed with advanced and/or incurable cancer types where a traditional chemotherapeutic approach is limited due to a high risk of toxicity to the dog. In some cases, metronomic chemotherapy may be equally as effective for a certain cancer type, thus is chosen due to lower risk of side effects.

Palliative treatment is intended to prevent tumor angiogenesis (spread of cancer blood vessels). The goal is not to cure the cancer or reach remission but to curb growth and extend life while maintaining quality of life. It should have minimal toxicity and is often cost‐effective, not to mention convenient.⁵

Maintenance therapy is used to keep the cancer from recurring or growing after a more intense protocol has had greater effect on the cancer. The intention is that it will offer a better quality of life than recurrent high dose protocols.¹

How Metronomic Chemotherapy Works

Metronomic chemotherapy was initially designed to overcome the development of resistance to chemotherapeutic agents, however, additional mechanisms of action have been uncovered over the past two decades:⁸

• Antiangiogenic effects keep the cancer from growing by selectively reducing the growth of new blood vessels around the cancer, limiting its ability to increase in size and/or metastasize.
• Immune modulatory effects can improve the immune system’s ability to fight off the cancer.
• Metronomic chemotherapy can induce tumor dormancy meaning that the cancer cells become less active, reducing cancer growth/spread.¹

In What Kind of Dog Cancers Is Metronomic Chemo Used?

Metronomic chemotherapy can be used for many different cancer types but has often been used for transitional cell carcinoma of the urinary bladder, nasal tumors, soft tissue sarcomas, and metastatic cancers.⁵

How to Get the Best Results from Metronomic Chemo Protocols

Your veterinary oncologist will give specific instructions for the exact medication or protocol that your dog is receiving. Here are some general guidelines:

• The clinician should have a definitive diagnosis of cancer type and choose the appropriate evidence-based chemotherapy protocol.
• The patient should undergo the appropriate staging tests (thoracic radiographs, abdominal ultrasound, complete blood count, biochemical profile, bone marrow aspirate, etc.) as indicated by the tumor type. Staging allows the clinician to evaluate the amount of disease present in a patient and guides treatment decisions.
• The patient should be stabilized as much as possible before treatment with a chemotherapeutic agent. Abnormalities in hydration, electrolyte balance, kidney function, liver function, and anemia should be corrected if possible.
• The owner should be made aware of the cost, schedule, and potential toxicities of the proposed treatment. The owner must be committed to the protocol for treatment to be successful.
• Other treatment options, if there are any, should be explored and discussed with your veterinarian¹⁰.
• Starting at the time of diagnosis, all oncology patients should have their nutritional status assessed and monitored. The dog’s diet may need to be adjusted to accommodate the unique nutritional needs of the individual dog, the specific cancer diagnosed, and any other diseases that the dog may also have (such as pancreatitis or kidney disease).³ Ensuring that all nutritional needs are met will help to support the dog’s overall health and prevent weight loss.
• A full inventory of supplements and medications that the patient is on should be verified to check for possible interactions with any chemotherapeutic drugs.¹¹ This includes alternative remedies such as homeopathy, as the interaction between cytotoxic drugs and most homeopathic remedies is not known⁴.

Home Care

The side effects of the chosen drug used in metronomic chemotherapy should be discussed with you by your veterinarian so you can be prepared for symptomatic treatment at home.

For example, if gastrointestinal signs such as vomiting or diarrhea are to be expected it would be best to have the needed medications on hand (anti-nausea, anti-diarrhea drugs) to treat the signs promptly.⁸

Follow Up to Metronomic Chemo Protocols

Frequent follow ups should be expected when using chemotherapy. You should expect blood tests to monitor your dog for any internal side effects such as kidney function decline, elevated liver enzymes, or a low white blood cell count. These tests may be more frequent in the beginning while your veterinarian is getting a sense of how your dog is handling the medications.

If using cyclophosphamide, frequent urinalysis of a voided sample should be expected as this drug has a risk of sterile hemorrhagic cystitis.³

Additional testing such as follow up imaging (radiographs, ultrasounds, CT scans) may also be useful in monitoring the response of the cancer to treatment.

When to Not Use Metronomic Chemo

Some cancers do not respond to metronomic chemotherapy drugs, so it is important to consider the odds of success versus the potential for side effects.¹³

Because many drugs are metabolized and/or eliminated by the liver and kidneys, animals with pre-existing renal or hepatic disease may experience increased toxicity or decreased efficacy. Dosages may need to be adjusted in these patients¹⁰.

Where to Get Chemotherapy Drugs to Use at Home

Metronomic chemotherapy will be prescribed through a veterinary oncologist or general practice veterinarian with experience using chemotherapeutic drugs. It is also important to recognize that referral to a variety of specialists may be needed at varying time points in the treatment process.³

Safety and Side Effects of Metronomic Chemotherapy in Dogs

Metronomic chemotherapy is usually well tolerated, but some side effects may occur:

• The most common side effect is gastrointestinal toxicities (diarrhea, vomiting, inappetence)
• Bone marrow suppression
• Alopecia (hair loss)¹⁵
• Chemotherapy resistance
• Sterile hemorrhagic cystitis, common in cyclophosphamide regimens (up to 32% of cases)¹
• Hematological toxicities such as thrombocytopenia, neutropenia, and anemia
• Liver and kidney damage¹⁶

If oral at-home treatment is the recommended course of action it is important to be aware that even in low doses chemotherapy drugs can be toxic. These drugs must be handled carefully. Chemotherapy pills (tablets and capsules) should be handled in a ventilated area or a respirator should be used to avoid inhalation of particles or aerosols³. Tablets should not be split or crushed and capsules should never be opened and divided. Suitable gloves should be worn while handling the drugs.⁴ If the chosen drug is cyclophosphamide, it is important to administer it in the morning, encourage water intake, monitor urine production and, if necessary, concurrently administer diuretics.¹ Patients should be monitored with bloodwork at their oncologist to check for bone marrow suppression. Complete blood counts (CBC) and serum biochemistry are typically checked once monthly throughout the treatment protocol.

Cost of Metronomic Chemotherapy for Dogs

The cost of metronomic chemotherapy is low compared to conventional chemotherapy, but depending on the drug, the frequency, and the size of your dog, it can still be costly.¹ Some estimations suggest that it can run between $100 and $600 dollars per month for the drug with additional follow-up testing and examinations added to that cost.¹⁷