In response to my note of last Friday (see: Genetic Testing to Cull Out the "Un-Right Patient" as a Candidate for a Particular Drug Therapy), Dennis Dionne submitted the following comment:
Chemotherapy drugs, i,e.; 5-fluorouracil (5-FU), are dosed by BSA [body surface area]. In the May 2008 issue of the Journal of Clinical Oncology, Dr E Gamelin reported a randomized multi-center study among metastatic CRC [colo-rectal cancer] patients treated with continuous infusion 5-FU whose drug blood levels were monitored and dosing adjusted to achieve target concentrations. Gamelin demonstrated that patients were over-dosed and only 25% were actually in the optimal range. By practicing therapeutic dose management (TDM) to maintain the plasma level of 5-FU within the therapeutic window, patients did much better. They experienced significantly better objective tumor response and doubling of survival at two years, while experiencing significantly less toxicity. Therefore, once the right patient is placed on the right therapy (genetic testing), therapeutic drug monitoring can make sure the right dose correlates with the right plasma level exposure to achieve optimal value.
A very relevant comment and I will return to this later.
In my mind, the definition of personalized medicine, also known as targeted therapy, is becoming more complex. The source of this additional complexity lies in the following new developments: (1) the growing importance of companion diagnostics; (2) the growing importance of medical imaging in both the diagnosis of disease, particularly tumors, and monitoring the efficacy of treatment; (3) the use of genomic and proteomic testing to cull out candidates for drug therapy who may be harmed by it; and (3) the use of medical imaging post initiation of chemotherapy to monitor its efficacy. The most obvious example of this latter approach is to determine with imaging whether a primary tumor or its metastases are shrinking.
Lets start this discussion of personalized medicine with what I considered to be a reasonable current definition from the Wikipedia presented below. To the right I also offer a diagram of an expanded flow diagnostic work flow diagram that encompasses some of the newly emerging nuances of personalized medicine, as I understand them. In the diagram, I include a box at the bottom to represent Dennis' very relevant comment about therapeutic drug monitoring (see above).
Personalized medicine [involves the] use of information and data from a patient's genotype, or level of gene expression to stratify disease, select a medication, provide a therapy, or initiate a preventative measure that is particularly suited to that patient at the time of administration. In addition to genetic information, other factors, including imaging, laboratory, and clinical information about the disease process or the patient play an equally important role.
In this diagram, I distinguish between "mandated lab companion testing" and additional genomic/proteomic testing because the former type of testing is frequently developed collaboratively by pharmaceutical companies and in-vitro diagnostic companies and often required or recommended by the FDA. The latter category may include newly discovered test methods that may clarify the therapeutic picture.
On the basis of this expanded understanding of personalized medicine (targeted therapy), I offer the following expanded definition that I have intentionally kept relatively brief for clarity:
Personalized medicine involves the use of laboratory-based molecular diagnostics and medical imaging to select suitable candidates for treatment with a particular drug(s), to rule out those patients who would suffer unacceptable side effects from the proposed drug treatment, and to monitor the health status of the patient post initiation of therapy to assess therapeutic drug levels and the continuing efficacy of the agent in suppressing or curing the disease.