Veterinary Cancer Specialists Blog

Robyn Elmslie, DVM DACVIM (Oncology)

Veterinary Cancer Specialists at VRCC

         Although bladder cancer comprises only 2% of all cancers in dogs, it is one of the most common cancers in middle-aged to older Scottish terriers, Shetland sheepdogs, West Highland white terriers and Beagles.  Clinical signs associated with bladder cancer are generally not apparent to pet owners until the cancer is very advanced.  Because of this, at the time of diagnosis most bladder cancers are very advanced and a cure is an unrealistic goal.  Instead, treatment focuses primarily on maintaining a good quality of life by controlling signs associated with the cancer, along with instituting therapies that delay cancer progression.  Survival times for dogs with bladder cancer are highly variable and depend on the site of the cancer within the bladder, the size of the tumor at the time of diagnosis, and on what type of treatment is administered.  Knapp et. al. (JVIM 1994) reported an average survival time of 6 months for dogs with bladder cancer treated with the NSAID drug piroxicam. Therapies in current use to further increase survival time include chemotherapy, radiation therapy and stent placement.

         Early detection of bladder cancer in dogs is very challenging.  In 2002, Billet et al (Am J Vet Res) published a study in which they evaluated a human bladder tumor antigen test to detect bladder cancer in dogs.  That study concluded that the test was not helpful for the differentiation of bladder cancer from other lower urinary tract diseases and therefore did not recommend the test for screening for bladder cancer.  However, in 2003, Henry et al (Am J Vet Res) published a study in which they evaluated the veterinary version of the bladder tumor antigen test (V-BTA).  In this study, they evaluated 229 client-owned dogs, 48 of which had bladder cancer and the remaining 181 dogs were either normal or had other types of bladder disease.  87% of dogs with bladder cancer had a positive V-BTA test and therefore the authors concluded that this test was indeed helpful for detection of bladder cancer in dogs.  As pointed out by Billet et al., the limitation of the V-BTA test comes when trying to differentiate bladder cancer from other types of bladder disease such as bladder infections or bladder stones.  In fact, the assay package insert recommends that the test not be used when there is blood or inflammation in the bladder as false positives are likely.  Thus, the V-BTA test had a high negative predictive value, but had a low positive predictive value.

So, what is the value of the V-BTA test?

The value of the V-BTA lies in the high negative predictive value of this test.  This means that when the test is read out as negative, there is a 90% chance that the patient does not have bladder cancer.  In breeds of dogs that are at high risk for developing bladder cancer, this test then becomes useful, as part of a geriatric wellness evaluation, to confirm that the patient’s bladder is normal. The test is best run on a mid-stream, voided urine sample collected in a clean plastic container.  It is not known how early bladder cancer can be detected with this test so it may be necessary to repeat this test 2-3 times annually to ensure that the results remain normal.  If the test becomes positive, further diagnostic testing is warranted to rule out bladder tumors or other diseases of the bladder.

For more information about cancers in dogs and cats please visit www.facebook/veterinary cancer specialits.com and www.vetcancerspecialists.com. 

Robyn Elmslie, DVM DACVIM (Oncology)

Veterinary Cancer Specialists at VRCC

Lymphoma is a lymph node cancer in dogs, similar to non-Hodgkin lymphoma in people, and affects approximately 15% of dogs with cancer.  It is rapidly progressive without treatment and very difficult to cure. Chemotherapy continues to be the treatment of choice for dogs with lymphoma.  The most commonly used chemotherapy protocols consist of a combination of chemotherapy drugs, most of which are given by injection. The goal is to combine chemotherapy drugs with different mechanisms of action for killing cancer cells, which in turn increases the probability of inducing a complete remission and long-term survival.  At the same time, combination chemotherapy protocols increase the time it takes for the cancer cells to become resistant to treatment.  Many variations of these multidrug protocols exist but the most widely used is a combination of doxorubicin, vincristine, prednisone and cyclophosphamide, known as CHOP. Treatment with CHOP has been reported to result in median remission times of 174 to 204 days  (Hosoya et al JVIM 2007; Simon et al JAVMA 2008) and to result in median survival times of 275-322 days. While some CHOP treated lymphoma patients have very short remission and survival times, 26% of dogs treated with CHOP live more than 2 years (Simon et al JAVMA 2008). 

Much research effort has been devoted to trying to understand why some patients with lymphoma respond so well to treatment, whereas others respond so poorly.  Several factors have been identified that negatively impact outcomes in dogs with lymphoma treated with chemotherapy.  One of the most important factors is the type of lymphocyte from which the lymphoma arises (Marconato et al. JAVMA 2011).  Lymphomas are broadly categorized into B-cell and T-cell lymphoma. It is generally accepted and widely reported in the literature that dogs with T cell lymphoma do much more poorly than dogs with B cell lymphoma, when treated with the CHOP protocol.  Beaver et al., first reported in 2009 (Veterinary Cancer Society Conference, Oct 2009), that one of the key drugs in the CHOP protocol, doxorubicin, was poorly effective for the treatment of T-cell lymphoma in dogs, and therefore may explain why dogs with T cell lymphoma have been reported to have short remission and survival times when treated with CHOP.  In their study, Beaver et al. treated 29 dogs with B-cell lymphoma and 12 dogs with T-cell lymphoma with doxorubicin as the first chemotherapy drug, to assess response to treatment.  Complete remission was achieved in 86.2% of dogs with B-cell lymphoma after just one treatment with doxorubicin whereas only 17% (2/12) of dogs with T-cell lymphoma achieved a complete remission after one treatment of doxorubicin. In a standard CHOP protocol, patients are treated with a different chemotherapy drug each week for the first 4 weeks of the protocol.  Doxorubicin is typically given on the third or 4 week of the protocol.  By this time, most patients with lymphoma, regardless of whether they have T or B cell lymphoma, are already in remission and therefore the actual benefit of doxorubicin in the CHOP protocol cannot be directly measured. 

Does this mean that dogs with T cell lymphoma should never be treated with doxorubicin or CHOP? 

Rebhun et al (VCO 2011) recently reported a median remission of 104 days and a median survival time of 235 days in 24 dogs with T cell lymphoma treated with CHOP.  In this study, Rebhun reported that 14% of patients lived one year and 5 % of patients lived 2 years. Brodsky et al (VCS 2009) reported more favorable results for patients with T cell lymphoma in a study of 50 dogs treated with an alternative protocol known as L-MOPP.  In this study, 25% of dogs with T cell lymphoma were reported to survive more than 2.5 years. 

There is not currently consensus in the Veterinary Oncology community regarding the best chemotherapy protocol for the treatment of patients with T cell lymphoma.  At Veterinary Cancer Specialists at VRCC, we continue to treat each patient as an individual.  There is not one approach that is best for every patient.  Many factors must be considered in making treatment recommendations.  As new research information becomes available, we incorporate that knowledge into our recommendations for our patients and their owners.  To learn more about Dr. Elmslie, the Oncology Team and cancer treatments, please visit www.vetcancerspecialists.com  and www.vrcc.com.  

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed in veterinary medicine, primarily for the treatment of arthritis and management of pain following surgery.  NSAIDs are also beneficial in improving quality of life, albeit short term, in both veterinary and human cancer patients by alleviating inflammation triggered by the cancer.

The mechanisms by which NSAIDs relieve inflammation and arthritis pain have been well studied and published.  The mechanisms by which NSAIDs alter cancer growth have been evaluated in cell culture but have not been widely studied in our veterinary patients. Knapp’s group first proposed treatment with the NSAID piroxicam (feldene) for dogs with cancer in 1992. They then reported (J Vet Int Med 1994) that of 34 dogs with bladder cancer, 6% (2/34) achieved a complete remission and another 12% (4/34) achieved a partial remission when treated with piroxicam. The mechanism of tumor cell killing by piroxicam was not determined in this study, and it has been speculated by some, although not confirmed scientifically, that the effect of piroxicam is primarily anti-inflammatory rather than a direct anti-cancer effect.  Nonetheless, it is clear that most dogs with bladder cancer have improvement in their symptoms when treated with piroxicam and therefore naturally live longer.

Piroxicam became the NSAID of choice for cancer bearing dogs and cats following the publication of Knapp’s bladder cancer study and another small study in dogs with oral cancer (JAVMA 2001).  In 2007 and 2008, our group published a study that evaluated piroxicam for the treatment of dogs with soft tissue sarcoma (Elmslie et al., JVIM 2008) and in dogs with hemangiosarcoma of the spleen (JVIM 2007).  In both studies, piroxicam in combination with other drugs was shown to significantly improve patient outcomes. However, the mechanism for the piroxicam benefit in these patient populations remains unknown.

While piroxicam seems to be the most effective NSAID for the treatment of veterinary cancer patients, in reality, other NSAIDs have simply not been widely evaluated and may therefore be more or less effective than piroxicam. In a recent study (JAVMA 2011), 24 dogs with bladder cancer were treated with the NSAID derocoxib (Dermaxx).  17% (4/24) of these dogs obtained a partial remission, similar to results reported in 1994 for dogs with bladder cancer treated with piroxicam.  The authors therefore concluded that the benefit of NSAIDs in dogs with bladder cancer was not restricted to piroxicam.  However, most veterinary medicine-approved NSAIDs, including carprofen (Rimadyl), tepoxalin (Zubrin), and firocoxib (Previcox) have simply not been evaluated for their antitumor activity in dogs or cats. 

While there is a plethora of studies describing possible anti-cancer effects of NSAIDs in cell culture, the anti-cancer effects of NSAIDs in cancer-bearing patients remains speculative. Our goal at Veterinary Cancer Specialists at VRCC is to maximize quality of life for each and every cancer patient.  NSAIDs play a big role in improving quality of life, at the very least, by reducing cancer-associated inflammation.  It should also be kept in mind that all NSAIDs have the potential for causing side effects, which then negatively impacts quality of life. Because the benefits of piroxicam are well-established, piroxicam is the NSAID that we most commonly prescribe, but only if well tolerated by the patient. When piroxicam is not well tolerated by the patient, or if the treatment goal is simply pain management, other veterinary medicine approved NSAIDs should be considered.

To read more about Dr. Elmslie, the Oncology team and cancer treatments in dogs and cats, please visit www.vetcancerspecialists.com and facebook/veterinary cancer specialists.

Robyn Elmslie, DVM DACVIM (Oncology), Veterinary Cancer Specialists at VRCC

The medical media has been abuzz about the possible harmful effects of omega-3 fatty acids since the September 2011 publication of a very interesting article in Cancer Cell by Roodhart et al.  In their study, the authors used mouse cancer models, to investigate mechanisms by which cancer cells become resistant to chemotherapy drugs.  This is an extremely important topic as chemotherapy resistance is a major obstacle to cures in both human and veterinary patients.  Through a series of well-designed experiments, the authors determined that when cancer cells were exposed to certain chemotherapy drugs, namely carboplatin and cisplatin, the patients’ own healthy stem cells were triggered to release two polyunsaturated omega-3 fatty acids that, within minutes, completely protected the cancer cells from the killing effects of the chemotherapy.

So what are the implications of this study for our patients? Polyunsaturated omega-3 fatty acids (PFA) are supposed to be the good guys, so does this mean that they should all be avoided in cancer patients? And are all chemotherapy drugs affected equally by these PFAs? 

Roodhart et al. were very careful to point out that not all fatty acids are implicated in triggering the chemotherapy resistance effect.  In fact, one of the most widely consumed omega-3 fatty acids (EPA), was confirmed to not have negative effects on chemotherapy killing of cancer cells in their models.  However, the two implicated polyunsaturated fatty acids, HHT and 16:4(n-3), are reportedly found in a wide variety of fish oil products and algae extracts.  When these products were fed to tumor bearing mice, even in very minute quantities, the same chemotherapy resistance was induced. 

On a recent trip to my local Vitamin Cottage, I identified 16 brands of fish oil that contained, in addition to EPA and DHA, unidentified omega 3 fatty acids, often listed as “other omega-3 fatty acids.”  It is these unidentified omega 3 fatty acids that we are proposing should be avoided until there is more research on the subject.

It must also be stressed however that there is no evidence, to date, that any of the omega 3 fatty acids from fish oil, have negative effects on cancer patients who are not undergoing chemotherapy.

In the case of cancer patients undergoing treatment with chemotherapy, only the platinum drugs, carboplatin and cisplatin, have been shown to trigger stem cells to release the fatty acids in question, however when mice were fed these fatty acids (HHT and 16(n-3)), resistance to multiple chemotherapy drugs developed.

Roodhart et al. also raised the issue of how cancer cells use the cancer patient’s own cells, in this case, their stem cells, to protect and promote their growth.  Stem cell therapy is an exciting new field in human and veterinary medicine and holds the promise of treating many devastating conditions such as arthritis and kidney failure.  While stem cell therapy may be very beneficial in the treatment of non-cancer bearing patients, this study is a cautionary tale of stem cell therapy’s potential deleterious effects in the cancer-bearing patient.

Finally, some good news!  Roodhart et al., found that the fatty acid induced resistance of cancer cells triggered by platinum chemotherapy drugs could be blocked by treatment with drugs that inhibit the COX-1 pathway, an example of which is the widely prescribed NSAID, piroxicam. Also, Bauer (JAVMA 2011) recently summarized the results of multiple studies in veterinary medicine documenting improved outcome from fish oil treatment in patients with a variety of conditions.

In summary, we recommend that pet owners review the labels of the fish oil supplements that they give to their pets when undergoing treatment with chemotherapy.  Fish oil containing unidentified omega 3 fatty acids should be avoided until chemotherapy is completed.   Stem cell therapy should also be avoided in cancer patients undergoing treatment with carboplatin or cisplatin. Treatment with COX-1 inihibitors or nonselective COX inhibitors such as piroxicam, may reduce chemotherapy resistance to carboplatin in cancer-bearing patients, but this needs to be confirmed with additional studies.

To learn more about Dr. Elmslie, the Oncology Team and our veterinary patients please visit http://www.facebook.com/VeterinaryCancerSpecialists

In a 2006 study published in JAAHA, Lana et al., interviewed 254 owners of cancer-bearing pets and found that 65% administered alternative therapy to their pets, most of which consisted of over-the-counter nutritional supplements, including anti-oxidants.  In a 2005 report, Yates et al. noted that 91% of human cancer patients implemented some form of alternative therapy, including nutritional supplements, while undergoing conventional cancer treatment. Despite this widespread use of antioxidants and nutritional supplements in both human and veterinary medicine, the medical community is divided about the potential benefits versus the potential harmful effects of these substances in patients undergoing cancer treatment.  In a 2011 article in the Journal of Evidence-Based Complementary & Alternative Medicine, Dr. Howes from John Hopkins Hospital writes, “Antioxidant vitamins have such widespread use that their potential to do harm has become a global public health issue.  We must follow the fundamental medical precept of Hippocrates: ‘‘First, do no harm.’’ We must separate fact from factitious and ‘‘myths of marketing’’ from scientific truths.” 

When it comes to antioxidants and nutritional supplements in pets and humans with cancer, the question bears asking:  What is the scientific truth and what is myth?

Numerous literature reviews have focused on the topic of whether supplemental antioxidants administered during chemotherapy or radiation therapy can protect normal tissues without negatively influencing tumor control.  Variations in study design, patient eligibility criteria, numbers of patients in the study, cancer type, and treatment protocols have all limited the ability of the authors to make definitive conclusions regarding the risk of decreased tumor control as a consequence of administering supplemental antioxidants during chemotherapy and/or radiation therapy.

Bairati et al. reported (JNCI 2005) that α-tocopherol (vitamin E 400IU/day) supplementation produced “unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival” in a randomized clinical trial of 540 human patients with head and neck cancer. Myung et al (Ann Onc 2010) reviewed the results of 22 randomized controlled trials in human medicine, which included 161, 045 total patients, 88, 610 in antioxidant supplement groups and 72, 435 in placebo groups.  Their analysis did not find any evidence of therapeutic benefit to the cancer patients but did identify an increase risk of bladder cancer, in 4 studies, in cancer patients taking antioxidant supplements.

It is therefore surprising that Simone et al. recently supported their 2007 published findings (AlternTherHealthMed) in which they concluded that antioxidants and other nutrient food supplements are safe and can help to enhance cancer patient care.  Of the 52 clinical studies Simone et al reviewed, 36 had many confounding variables that prevented drawing any clear conclusions.  Of the 16 randomized controlled trials they cited, all included 100 or fewer patients, a sample size that may be too small to draw conclusions about outcome.  In fact, Lawenda et al (JNCI 2011) determined that a statistically meaningful study would require the inclusion of approximately 2,000 patients in order to identify a 5% change (increase or decrease) in survival time as a result of antioxidant supplementation in cancer patients undergoing chemotherapy and/or radiation therapy.

While there is no consensus about the effects of antioxidants in improving or negatively impacting treatment outcome, there does appear to be consensus in the medical community that the use of antioxidants and nutritional supplements can improve chemotherapy and/or radiation therapy side effects in some patients.  

At Veterinary Cancer Specialists at VRCC, we take a cautious approach to the use of anti-oxidants and nutritional supplements. The bottom line is always the quality of life of our patients.  If treatment is well tolerated, as it usually is, and the patient is in good physical condition with a good energy level, antioxidants and nutritional supplements may not be necessary.  If chemotherapy and/or radiation therapy is not well tolerated, anti-oxidants and nutritional supplements may allow improvement in treatment tolerance, ultimately allowing for a better survival outcome.

To read more about our Oncology Team and cancer treatments in dogs and cats, please visit facebook.com/VeterinaryCancerSpecialists and www.vrcc.com.