How do we know which chemotherapy drug works best in the treatment of cancer? I guess the "proof is in the pudding." Wait a minute! Where did that silly phrase come from? And what does pudding have to do with chemotherapy? After a bit of searching in a real library (rather than on Google), I found the quotation in the comic novel "Don Quixote" written by Miguel de Cervantes in 1615. The phrase is actually written as, "The proof of the pudding is in the eating." In the context of Don Quixote, it means that the true value or quality of something can only be judged when it's put to use. It's the result that counts. Nearly 300 years later, in 1890, the German physician Robert Koch applied the "pudding principle" in his microbiology laboratory. He devised four steps, now known as Koch's postulates, on how to prove a microbe was responsible for a particular illness. We refer to his postulates when proving cause and effect relationships. Modern day chemotherapy began near the start of World War II when Yale scientists were asked to study chemical warfare agents. Their research showed that a cause-and-effect relationship existed between an administered dose of nitrogen mustard gas and the destruction of lymphatic and bone marrow tissues. They reasoned that this might have value in the treatment of lymphoma. While many rodent and rabbit experiments showed promise, in December 1942, a 48-year-old patient with lymphoma was given the first chemotherapy treatment. Within two days, a regression of the man's lymphoma was noted and he eventually obtained a complete remission. Proof of Concept While it appears there are many agents available to manage cancer patients, the number is actually quite small. Hundreds, if not thousands, of chemicals are tested annually for possible anticancer benefits. Few make it through the proof-of-concept approach that allows researchers to demonstrate the feasibility that an agent will probably work in a useful manner against a particular cancer type. In the proof-of-concept approach, the agent must first prove itself against tumor cells in vitro and tumor cells implanted in rodents, and also prove that it does not create overt toxicity in animals. If the agent shows promise and if the "proof of the pudding is in the eating," then the next step is crucial to the success of the agent - administration to a person with cancer. Generally the agent is given as monotherapy in a dose-escalation method (Phase I study). While the desired endpoint is efficacy, the true endpoint is determining a maximum-tolerable dosage for future testing of the agent in additional people with cancer (Phase II study). Scientific Pitfalls There are many scientific pitfalls with the proof-of-concept approach that result in inappropriate rejection of an anticancer agent. During the in vitro evaluations, the success or failure of the agent is dependent upon the investigators' selection of an appropriate target cell line and testing under appropriate pharmacokinetic conditions. For example, cyclophosphamide is a well known and effective anticancer agent. However, it has little to no direct cytotoxic effect in vitro because it requires enzymatic activation. Another pitfall occurs during the rodent evaluations. Variations in protein binding of the agent, pharmacological activation or elimination of the agent or variations in drug uptake by the tumor cell population may influence the success or failure of the agent. Then, if the agent makes it to the Phase I or Phase II level of study, starting dosages are usually subtherapeutic with the optimum dose delivery and interval unknown. Additionally, the health of the subject, generally one with end-stage, treatment-refractory cancer, can influence agent results. There are many ethical and financial concerns that may also influence the success or failure of an agent in the proof-of-concept approach. Putting Theory to Practice So how do oncologists know which chemotherapy drug works best in the treatment of cancer? Well, we actually don't. What we do know is the action of an anticancer agent during a unique set of circumstances. For example, we know that when we administer doxorubicin (Adriamycin) at a dosage of 30 mg/m2 intravenously to a dog with multicentric lymphoma (most likely B cell type), the conditions will be favorable for an anticancer response. We also know that administering the same drug at the same dosage to a dog with a cutaneous lymphoma (also likely a B cell type) is unlikely to work. What causes the difference between the two? Many clinical investigations in veterinary oncology come from trial and error without a complete understanding of the genetic and biological differences within the cancer cell population. We seek the broadest spectrum of activity of the anticancer agent rather than an understanding of the basics of each disease. So if the point of Cervantes' quote in "Don Quixote" is that the end result matters most, how do we eradicate cancer? The "proof of the pudding" will come from those results obtained by research by geneticists and translational research laboratories with a promise for effective, novel and possibly patient-specific targeted treatments, not from the use of the "best" chemotherapy agent available. --- Kevin A. Hahn, DVM, Ph.D., Dipl. ACVIM (Oncology), is director of Oncology Services at Gulf Coast Veterinary Specialists, Houston (www.gcvs.com/oncology), and is the oncology consultant for YourNetVet.com.
