Testing Whether Precision Dosing Improves Clinical
Outcomes
TDM feasibility trials can demonstrate that TDM-guided dose
individualization is effective in optimizing drug exposure, but they are
not designed to prove that TDM actually improves treatment outcomes.
Nevertheless, these studies are essential for test-driving
dose-adjustment protocols, workflows, and infrastructure, as well as for
identifying unforeseen barriers to execution of dose-adjustment
recommendations. Consequently, the parameters derived from TDM
feasibility trials are critical for informing the design and
implementation of subsequent randomized controlled trials (RCTs) for
testing whether dose individualization improves treatment outcomes
(Figure 1, Stage 4). Based on TDM feasibility trial data, much
consideration during the design of the RCT should be given to defining
the comparison groups and the criteria for inclusion and exclusion of
subjects with respect to the population of patients most likely to
benefit from TDM. For example, it may be prudent to select only those
individuals who are over- or under-exposed as your study population,i.e. those at high risk of treatment failure due to lack of
efficacy or toxicity, rather than comparing outcomes for “TDM” vs “no
TDM” in all patients receiving the drug.
One possible concern related to conducting a randomized controlled trial
comparing TDM with the standard of care (i.e. no TDM) is that
some may consider it unethical to abstain from increasing the drug dose
in control patients with low systemic exposure. The underlying
assumption in such an argument is that increasing the drug dose in an
under-exposed patient will improve the clinical outcome. Based on this
assumption, however, it may further be argued that it would be unethical
not to measure drug levels in all patients to identify the underexposed
individuals who would benefit from dose increases, and the ethical
solution may be to apply TDM universally.33 A
“catch-22” of sorts, this assumption is exactly what the randomized
controlled trial in attempting to prove! Without RCTs demonstrating
clear benefits of TDM versus no TDM for at least some oral small
molecule anticancer drugs, the current oncology practice will not have
enough incentive to change and all underexposed patients receiving the
standard of care will continue to be prescribed sub-therapeutic doses of
these drugs. For example, at our institution there are approximately 550
patients with active imatinib prescriptions. Despite evidence to suggest
that approximately 150 to 350 of these individuals may be under-dosed
(~25%-65%),29,36,37 our laboratory
receives fewer than 3 samples per week for imatinib level monitoring.
To the best of our knowledge, there is no randomized controlled trial,
either published in a peer-reviewed journal or ongoing, that uses a
clinical outcome as the primary endpoint and demonstrates the benefit of
TDM of targeted oral anticancer drugs. Nevertheless, results from
several trials have been published in abstract form only, and thus may
need to be considered with caution. Rousselot et al. reported the final
results of the randomized OPTIM Imatinib study, which demonstrated that
TDM increases the rates of molecular response in patients with chronic
myeloid leukemia (CML).36 Another abstract from the
same group reported that TDM of dasatinib resulted in reduced risk of
pleural effusions and high molecular response rates in
CML.38 Results of a trial by Gotta et al. were
published in a peer-reviewed journal, but this study did not compare TDM
versus no TDM. Instead, “routine TDM” was compared to “rescue TDM”
for Imatinib in 57 CML patients.24 The primary
endpoint was a combined outcome (failure- and toxicity-free survival
with continuation on imatinib) over 1-year follow-up. This dose
individualization trial could not demonstrate additional benefit of
“routine TDM” using intention-to-treat analysis, due to a small number
of study participants and, surprisingly, limited prescribers’ adherence
to dosage recommendations. However, using as-treated subgroup analysis
of “routine TDM” group, 10 of 14 of patients receiving the recommended
dosage after one cycle of TDM remained event-free compared to 3 of 13
patients for whom dosage recommendations were not correctly adopted
(P=0.033).
Thus, despite numerous studies (primarily in Stages 1-3 of Figure 1)
providing evidence to suggest that TDM of oral small molecule anticancer
drugs may be beneficial to patients, and perhaps even
cost-effective,39 there seems to be no published study
that definitively demonstrates such benefit. Historically, there are
examples of drugs, such as calcineurin inhibitors, for which TDM became
the standard of care without demonstrated superiority of “TDM” vs “no
TDM” in RCTs. However, in the present culture emphasizing
evidence-based medicine, having more drugs reach stage 4 of Figure 1
must be the goal, as this will encourage requests for TDM by medical
oncologists as well as increase the chances for reimbursement of costs.