Individualized Treatment
Introduction
It is well established that brain tumors with the same histopathological diagnosis (eg, GBM) are genotypically and phenotypically heterogeneous between patients (intertumoral heterogeneity) (eg, Pedeboscq et al 2007), and also heterogeneous across the cells within a given tumor (intratumoral heterogeneity). Moreover, the genotypic/phenotypic profile of a given tumor can change over time due to tumor evolution. For these reasons, it is desirable to select treatments most likely to be effective considering the specific profile of each patient's tumor at a given time. This approach is known as "individualized" or "personalized" treatment.
Tumor Molecular Testing
Tumor molecular testing can be used to help identify which specific treatments (especially targeted agents) and combinations of treatments might be most effective (or not) for each individual patient. See Mischel et al 2004, Mellinghoff et al 2005, Jeuken et al 2006, and Mischel and Cloughesy 2006 (a short overview), de Groot and Gilbert 2007, and TCGA 2008.
However, such testing is still under development, is offered by only a limited number of facilities, and is not yet part of the standard of care (see Lassman and Holland 2007). Moreover, intratumoral heterogeneity and tumor evolution can reduce the longer-term usefulness of molecular testing (see Wager et al 2008), and may even prevent targeted monotherapies from ever being curative "magic bullets."
Optimizing Chemotherapy Selection
Conventional cytotoxic monotherapy, by virtue of being relatively nonspecific in comparison with targeted monotherapy, may have greater probability of providing cure for at least a small percentage of patients, although the probability is indeed low for currently available treatments (eg, TMZ).
To help optimize the selection of chemotherapy on an individualized basis, see Iwadate et al 2003 for an in vitro assay; Parkinson et al 2008 for study of DNA repair mechanisms; and Humor Tumor Assay Journal, Weisenthal 2003, Hwu et al 2006, Rational Therapeautics, and Remission Labs for information on chemosensitivity testing.
Combination Therapy
Use of combination therapy is likely to further increase the cure rate in comparison with monotherapies. However, a monotherapy such as a particular targeted agent may still target most cells within a tumor, and may therefore significantly extend survival and have clinical value, even if it has limited potential to be curative (due to the remaining tumor cells which are not targeted).
Tumor Stem Cells
A further consideration is that, if the tumor stem cell hypothesis is correct, it would appear necessary that curative treatment must specifically target the tumor stem cell subpopulation, and possibly also any cells from which tumor stem cells are derived, particularly cells which might de-differentiate into tumor stem cells. The tumor microenvironment may play a significant role in these processes (see Bissell and LaBarge 2005).
Adaptive Therapy
It may be possible to effectively address some of the obstacles noted above through an adaptive approach to treatment in which tumor testing is repeated at regular intervals, with treatment then regularly adjusted to track the changing profile of the tumor (see Freidlin and Simon 2005, Zhou et al 2008, and dynamic treatment regimes (Wikipedia) for related approaches).