Cancer chemotherapy – Then, Now, and the Future

In 2016, an estimated over 1.5 million new cases of cancer will be diagnosed in the United States and almost 600,000 people will die from the disease.1 On the veterinary side, there are approximately 65 million dogs and 32 million cats in the United States, with roughly 6 million new cancer diagnoses made in each dogs and cats annually.2 Although we often see ourselves in the veterinary world as “catching up” to the human side, veterinary cancer medicine has actually co-evolved with human cancer medicine. November is Pet Cancer Awareness month, which is always a good time to reflect upon our progress and standing as a profession. The following provides a (rather) abbreviated overview of where we started, where we are, and where we’ve still yet to go.

Historical accounts of human cancer date back some 5000 years ago to the scribes of Egyptian physicians.3 These records included descriptions and illustrations of uterine and breast cancers and the physical suffering they caused. Ancient physicians used a variety of terms to describe tumors, including ‘‘carcinos’’, the Greek word for crab, which alluded to the crab leg-like extensions emanating from breast tumors, and “onkos”, the Greek word for swelling.3 Obviously these terms and derivations of them are still with us today. Although their observations were astute, the early Greeks’ initial approach to cancer treatment was rudimentary. Surprisingly, this undeveloped methodology remained static over the following centuries and cancer treatment consisted of surgery, cautery, blood-letting, and herbal medicines only.3 Fortunately, science and technology advanced enormously once the 1700s came around, however, it was still not for over 200 years that chemotherapy became established as a legitimate tool of modern cancer medicine.

Paul Ehrlich, a German physician known as the “Father of Chemotherapy”, coined the term chemotherapy and was one of the earliest pioneers to screen medicinal chemicals in animals.3 In 1915, Germany – the home nation of Ehrlich – became the first country to use mustard gas on the battlefield during World War I. It is actually upon this act of war that the era of modern chemotherapy is founded. Almost 100,000 people lost their lives to this poison gas during the war. Fortunately, several autopsies were performed and found that mustard gas exposure caused severe lymphoid depletion, neutropenia, and bone marrow aplasia. Unfortunately, it took 20 more years before the idea of therapeutically using mustard compounds was realized. The chemical research that went on following the war found that nitrogen mustard, a close but less toxic derivative of mustard gas, had antitumor activity against lymphoma in mice. Then in 1943, a mustard compound was used for the first time in a patient with non-Hodgkin’s lymphoma at Yale University Medical Center. Impressive, but only temporary, regression was observed in this and subsequent lymphoma patients. Then in 1947, aminopterin, a folate analog initially used for pernicious anemia, was first used by Dr. Sidney Farber to treat pediatric patients with leukemia. His successes were met with a lot of resistance, but eventually led to expansion of cancer medicine and the discovery of several other chemotherapy agents, including methotrexate, vinca alkaloids, and procarbazine, in the 1950s-60s. 3

In many ways, veterinary medical oncology has closely followed the advances in human medical oncology. For example, the first reported use of chemotherapy in a veterinary cancer patient (a dog with lymphoma treated with urethane) was in 1947, the same year Sidney Farber treated his first pediatric patient with aminopterin. The first use of asparaginase for treatment of canine lymphoma was reported in 1967. During these early years of development of veterinary chemotherapy, single agent chemotherapy was still the standard of care in human oncology until the MOPP (Mustargen, Vincristine, Procarbazine, Prednisone) combination protocol was developed in the mid to late 60s. The first reported use of combination chemotherapy for canine lymphoma involved chlorambucil plus prednisone and was published in JAVMA in 1968. A far more sophisticated combination chemotherapy protocol for canine lymphoma using 5 different drugs was reported in 1975. The first report of doxorubicin use in dogs was published in the veterinary literature in 1976. In time, this drug became the backbone of multidrug protocols for a wide variety of canine and feline tumors. The evolution in sophistication of the drug protocols used in dogs mirrored what was transpiring in human medical oncology at about the same time. However, as in human cancer medicine, the problem of drug resistance in veterinary oncology is very real and typically the limiting factor in being able to successfully eradicate individual cancers with conventional chemotherapy alone. This problem may be even more magnified in veterinary oncology given the limits (natural and applied) on chemotherapy dose intensity.

Over time, researchers have uncovered the fact that cancer can arise from any number of genetic aberations, and often is due to a combination of errors that ultimately lead to unregulated cell growth. Now, with dramatic improvements in DNA technology, researchers and physicians can analyze an individual patient’s tumor to determine what genetic abnormalities are present. Using genomic profiling, instead of simply applying the broad-brush approach of surgery, radiation, and one-size-fits-all chemotherapy protocols for specific cancers, physicians can now more accurately match targeted treatments to individual patients. For some cancers, the protein products of genetic mutations are identifiable targets in cancer cells that can be “blocked” with specific drugs. Such molecularly targeted drugs have provided patients, in particular those with advanced disease, an option to help control cancers that have failed traditional chemotherapies and radiation. This is what personalized medicine is all about, and this is also becoming more readily applicable in veterinary medicine. A still fairly recent and no doubt exciting development in veterinary chemotherapy was the introduction of toceranib phosphate, also known as Palladia, by Pfizer (now Zoetis) in 2009. This drug was the first targeted chemotherapy agent developed specifically for dogs and is FDA-labeled for the treatment of advanced canine mast cell tumors, although its current application in veterinary oncology spans several tumors types in both dogs and cats.4 Although molecularly targeted drugs are certainly a step forward, they too are not a cure-all, as there are mechanisms of resistance and evasion by cancer cells to these drugs as well.

Potentially the most promising approach in clinical cancer medicine is immunotherapy. This modality incorporates a patient’s own immune system into the fight against the tumor, oftentimes along with radiation, chemo, and targeted molecular therapies. Immune-based therapies involving monoclonal antibodies, checkpoint inhibitors, cytokines, and many others, have already transformed the treatment for several human cancers. These are therapies that we are now evaluating in companion animals and gradually adding to our arsenal for veterinary cancers. In veterinary medicine, we have Merial’s Oncept®, a USDA-approved vaccine against malignant melanoma that has significantly improved outcomes for dogs with this highly aggressive cancer.5 While initial attempts at developing monoclonal antibodies against canine B-cell and T-cell lymphoma have thus far fallen short, several companies have gone back to the drawing board and are working on second-generation monoclonals with the intent of developing the veterinary version of rituximab (Rituxan®), the monoclonal antibody that has revolutionized the treatment of B-cell lymphoma in people.

Other areas of interest in veterinary cancer research include bone marrow transplantation, complementary and alternative therapies such as herbals like Yunnan Baiyou and polysaccharopeptide (PSP), an extract from the mushroom coriolus versicolor and the key ingredient in I’m Yunity®,7 acupuncture, and diet therapy.

Undoubtedly, light years of progress has been made since mustard gas was first used in World War I, yet as we all know, we still have so much further to go in the war against cancer.

Submitted by Christine Mullin, VMD, Diplomate ACVIM (Oncology)

References

  1. National Cancer Institute. Cancer Statistics. https://www.cancer.gov/about-cancer/understanding/statistics
  2. National Cancer Institute Center for Cancer Research. Comparative Oncology Program, For Pet Owners. https://ccr.cancer.gov/comparative-oncology-program/pet-owners/what-is-comp-onc
  3. Morrison WB. Cancer Chemotherapy: An Annotated History. J Vet Intern Med 2010;24:1249–1262. http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2010.0590.x/full
  4. London CA, Malpas PB, Wood-Follis SL, et al. Multicenter, Placebo-controlled, Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Excision. Clin Cancer Res 2009;15(11):3856-3865. http://clincancerres.aacrjournals.org/content/15/11/3856.long
  5. Bergman PJ and Wolchok JD. Of Mice and Men (and Dogs): development of a xenogeneic DNA vaccine for canine oral malignant melanoma. Cancer Ther 2008; 6:817-26.
  6. Griffin MM and Morley N. Rituximab in the treatment of non-Hodgkin’s lymphoma – a critical evaluation of randomized controlled trials. Expert Opin Biol Ther 2013;13(5):803-11. https://www.ncbi.nlm.nih.gov/pubmed/23560506
  7. Brown DC and Reetz J. Single agent polysaccharopeptide delays metastases and improves survival in naturally occurring hemangiosarcoma. Evidence-based complementary and alternative medicine 2012; Article ID 384301:1-8. https://www.hindawi.com/journals/ecam/2012/384301/

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