More About Chlorambucil, Cyclophosphamide for Metronomic Chemotherapy

Is your oncologist recommending low-dose, metronomic chemotherapy for your dog or cat to help fight cancer? If so, one of the most common chemotherapy agents, chlorambucil (aka: Leukeran) or cyclosphosphamide (aka: Cytoxan) will likely be part of your regimen.

Oncologists will often choose a metronomics chemo drug based on their familiarity and successes with that drug. For example, in our recent interview with Dr. Barbara Biller, Veterinarian and Associate Professor of Oncology at Colorado State University Animal Cancer Center, she explains why cyclosphosphamide is her preferred choice for metronomics.

Today we’ll learn why chlorambucil is the preferred metrnomic chemotherapy drug of choice for Dr. Joanne Intile DVM, DACVIM/Oncology, at the VCA Veterinary Referral Associates in Gaithersburg, Maryland.

We are grateful for Tripawds member Jill‘s help in recruiting Dr. Intile for the following interview, in which Dr. Intile discusses her experience using chlorambucil in metronomic chemotherapy.

Be sure to follow Dr. Intile’s blog at the Daily Vet for more news about metronomic chemotherapy and other cancer treatments for pets.

Dr. Intile Discusses Chlorambucil (Leukeran) for Metronomics

How long have you been using Leukeran?

I’ve been using Leukeran (chlorambucil) to treat a variety of cancers, typically blood borne cancers such as lymphoma and leukemias for as long as I’ve worked as a veterinarian. I’ve been using this drug in my metronomic protocol for about 3 years now.

Which clients do you put on metronomics? Are they in remission, experiencing metastasis, or both?

Since metronomic chemotherapy is designed to prevent or delay blood vessel growth to tumor cells, I feel it’s best utilized in patients where we suspect microscopic cancer cells are present, but they are below the level we are able to detect them. There are two studies that I think are good examples of using metronomic chemotherapy in that exact setting. One looked at dogs with splenic hemangiosarcoma and one looked at dogs with soft tissue sarcomas.

Splenic hemangiosarcoma is a very aggressive type of cancer in dogs, and even when the primary tumor is removed via splenectomy, most dogs will go on to develop metastases within just a few short weeks to months after surgery. So we know that once the spleen is taken out, there are microscopic cells present in other organs, but we just cannot detect them.

Soft tissue sarcomas typically present us with the exact opposite challenge. They are extremely difficult to remove in their entirety with surgery, but usually have a low chance of spread. So even with aggressive surgery, it’s very likely microscopic cells were left behind right at the tumor site. Though not perfect in their design, in those studies, dogs that underwent treatment with metronomic treatment survived longer and had longer time to tumor progression than when treated with surgery alone.

I think the best use of metronomic therapy is in cases where the primary tumor is adequately controlled (e.g. with surgery and/or radiation therapy) and there is no evidence of spread AND that patient has undergone the current standard of care of treatment. For me, the best example would be a dog with appendicular osteosarcoma, which underwent limb amputation and full course injectable chemotherapy. We know that even with such aggressive treatment, most of those dogs will still go on to develop spread later on and succumb to their disease. I recommend metronomic treatment in those cases.

I will also use it in cases where the pet isn’t a good candidate for conventional chemotherapy, or when owners simply can not travel to the hospital to see me as frequently as would be required for other protocols.

I also will use it in cases where visible tumors are detected (e.g. metastases) and the pets are still feeling well. Those are the most challenging cases to treat with chemotherapy, and the major limitation to using metronomic chemotherapy in this setting is once you can detect a tumor, it probably has grown a very decent blood supply of it’s own, and your chance of slowing that down is going to be less (but not impossible). In such cases, owners must be willing to monitor their pets very closely so we can be sure the treatment isn’t causing harm, and to be sure we are truly seeing a benefit from the treatment.

What is the protocol you usually prescribe (what combo of drugs/supplements for her version of metronomics?

The typical protocol I employ for dogs is an oral non-steroidal anti-inflammatory drug combined with oral alkylating chemotherapy drug called chlorambucil (Leukeran). The non-steroidal is typically administered daily, while cyclosphosphamide is given every other day. I will typically prescribe feldene (Piroxicam) as my first line non-steroidal, but for dogs that have received other non-steroidal drugs and tolerated them without complication, I will use that instead. Feldene is a human drug, while others such as carprofen (Rimadyl/Rovera), deracoxib (Deramaxx), meloxicam (Metacam) are all veterinary approved versions of non-steroidal anti-inflammatory drugs. Chlorambucil is also a human drug, and only is formulated in 2mg tablets. They cannot be crushed or split, and can be quite expensive. This makes dosing for veterinary patients challenging. So I will usually have this drug compounded, which means I will prescribe it through a special pharmacy where it can be made into capsules of exactly the size I need for my patients.

For cats, I will also prescribe leukeran. We know cats tolerate this drug really well, but I’m a little more cautious about using non-steroidal in cats as they can cause renal (kidney) damage.

A very important aspect of treating cases with metronomic chemotherapy is making sure owners understand this is chronic therapy that requires chronic monitoring. Since this form of treatment is relatively new for us veterinarians and we don’t really know what adverse effects are possible, it’s important to watch patients carefully and recognize early signs of drug intolerance before the animals are showing adverse effects.

What prompted you to start choosing leukeran over cytoxan?

When I first started prescribing metronomic chemotherapy, I used the conventional alkylating chemotherapy drug called cyclophosphamide. When you use this drug in metronomic protocols, the dose is much lower than would be administered in a single dose given orally or intravenously (~ 20X’s less).

We know that one of the potential side effects of full dose cyclophosphamide is something called sterile hemorrhagic cystitis. This is caused by an inactive metabolite of the drug called acrolein. Acrolein causes irritation and damage to the cells lining the bladder, resulting in intense inflammation. This condition is called sterile hemorrhagic cystitis (SHC).

Affected animals can show signs just like they would have a urinary tract infection: straining to urinate increased frequency and urgency of urination, and blood in the urine. This is quite painful for them and since there is no bacterial cause for the condition, there is really no effective treatment for the signs.

The chance of this happening to a dog receiving cyclophosphamide at full dose is only about 10%. When full dose cyclophosphamide is administered along with a diuretic drug such as furosemide (Lasix), the risk drops to less than 2%. The diuretic acts to make the dogs drink and urinate more frequently so the acrolein doesn’t have time to sit in the bladder and cause damage. If SHC develops in a dog using a chemotherapy protocol with cyclophosphamide in it, the recommendation is to discontinue cyclophosphamide and treat with chlorambucil.

Since the dose of cyclophosphamide used in metronomic protocols is much lower than full dose, it was thought the risk of SHC would be low. When the initial studies looking at the efficacy of metronomic cyclophosphamide came out, the reported chance of SHC was roughly between 10%-20%.

When I first started using metronomic chemotherapy, I employed cyclophosphamide as my chemotherapeutic of choice. Well, I must have tremendous bad luck, because the first 4 dogs I placed on this protocol developed SHC. They each showed signs of urinary incontinence, hematuria (blood in their urine), stranguria (straining to urinate), and dysuria (pain on urination). I tried treating them with anti-inflammatory drugs, pain medications, antibiotics, and I found my success was really low. With time, they all recovered – some within a few weeks, and one took 3 months. To me, seeing these animals essentially frightened me too much and so I decided to use chlorambucil instead, and I’ve never looked back.

Cyclophosphamide and chlorambucil are not the same drug, and yes, there may be a compromise of efficacy in doing so. But our golden rule in veterinary medicine is to “First Do No Harm”; therefore substitution is the safest option for any pet experiencing SHC from cyclophosphamide, and for me, the best way to ensure this complication does not arise.

How have your patients responded to leukeran? Can you cite any longevity statistics?

I think the vast majority of my patients do fantastic on metronomic chlorambucil. Side effects in both cats and dogs are very rare. I monitor them closely for signs of low white blood cell counts, kidney and liver damage, and any other labwork abnormalities. We pay attention to their appetite, energy, and body weights. If there are any signs of intolerance we can stop treatment and re-evaluate them.

As far as longevity statistics, that’s a tough one. I have one dog with a metastatic tonsillar squamous cell carcinoma that went through aggressive surgery, radiation therapy, chemotherapy, and has now been on metronomic chemotherapy for just over one year. I gave his owner a very grave prognosis when I first met him almost 2 years ago and today he lives to try and bite me every time he comes in for a recheck. I also lost a dog to osteosarcoma this week about 10 months after his diagnosis, who also went through aggressive surgery, chemotherapy, and had started on metronomic treatment only 3 months ago.

I think metronomic treatment is a very promising area for us in veterinary medicine and I am looking forward to the research that will be coming out in the near future regarding this form of treatment.”

Let’s give 3-paws up to Dr. Intile for helping us spread the word about chemotherapy choices for Tripawds and all animals. Remember, always talk to your own veterinary oncologist about any cancer treatments you wish to pursue or learn more about for your dog or cat.

Recommended Reading

The Daily Vet: Understanding Metronomic Chemotherapy Cancer Treatment for Pets

Tripawds News Blog: Cyclophosphamide Versus Chlorambucil in Metronomic Chemotherapy
Tripawds Downloads Blog: Metronomic Chemotherapy News Podcast on Tripawd Talk Radio
Tripawds Discussion Forums: Metronomic Chemotherapy for Canine Osteosarcoma
Tripawds Discussion Forums: Jackson’s Urinary Cystitis
Tripawds Discussion Forums: Jill’s Metronomic Chemotherapy Experience