Dr. Norris: A new
concept may help us at last abandon one-size-fits-all dosing of
cancer treatment drugs
What is it about?
"With many medicines, it is obvious to doctors and patients alike
that different people require different doses, and that we cannot
predict exactly the right dose for each person before giving the
first dose. Thus, a process of gradual dose adjustment over time is
needed to learn what dose strikes the best balance between the good
and bad effects of the medicine in each individual. Many people who
take drugs for high blood pressure, low thyroid or epilepsy will
recall having to adjust their dose one or more times when they first
started. Certainly, many people with diabetes who inject insulin are
experts in this concept, since they are actively involved with dose
titration every day of their lives.
This paper is about applying this very same principle to cancer
treatment drugs. Currently, a 'one-size-fits-all' mentality
dominates dosing in oncology, and this approach gets established
very early in the drug development process. The first use of most
cancer drugs in humans occurs in people with cancer who have not
been doing well despite having tried all standard therapies. People
in this situation are often willing to try an experimental drug,
even when doctors have no experience to guide them in choosing a
dose. The aim of these early 'Phase 1' studies is conceived of as
finding 'the' Maximum Tolerated Dose (MTD)—as if there were a single
right dose for everyone. Despite its obvious flaws, this fallacy
persists because statistical methods have not been available to help
us see past it. The aim of this paper is to provide such methods,
and to put them in a conceptual context that makes them feasible to
implement in clinical trials and in clinical practice.
Why is it important?
For 2 decades, evidence has been accumulating that patients who have
adverse effects from their chemotherapy actually tend to get better
results from it. (Please see https://www.zotero.org/groups/1150255/the_mtd_kills,
where I have collected a list of dozens of journal articles relating
to this.) This is not surprising, of course, since the adverse
effects experienced by these patients would also have 'hurt' their
cancer cells—which is the whole point of chemotherapy. What this
means, however, is that better ways of safely finding the strongest
acceptable dose for each patient will give people with cancer their
best chance to benefit from treatment. This is obviously directly
important to each individual person with cancer, but it is also
indirectly important for society because inadequate dosing in Phase
2 and Phase 3 clinical trials might stop good drugs from getting
approved by regulatory agencies."
Escalation Methods in Phase I Cancer Clinical Trials
Christophe Le Tourneau J. Jack Lee Lillian L. Siu
JNCI: Journal of the National Cancer Institute, Volume 101,
Issue 10, 20 May 2009, Pages 708–720
On the importance of
the dose, and how cancer drugs work - or not work - in the body:
in the northeast a storm is brewing,
bringing hurricane force winds, accumulating snow … blizzard
conditions. For snow to accumulate, the intensity and duration
must be sufficient for the crystals to reach earth, to stick, and to
build up faster than they evaporate or melt.
... These are principles that apply pretty well to the behavior of
drugs in the body that are investigated as a first step when a drug
is tested in human subjects. Having a basic understanding of
the importance of getting the dose right in clinical research, you
will know what to expect in a phase I clinical trial … and also what
questions to ask when advised to take an herb to treat a cancer.
study compound (to have a chance to be active) must get to the blood
– the vehicle for distribution of the compound to the cells in our
body. Then, to have biologic activity, the compound must stick to
something … ideally to a part of the cell involved in the malignant
behavior, such as a receptor (on the cell), or a pathway (in the
cell) that drives the abnormal growth or persistence. Affinity
for the target is also important. Affinity is how well the
compound binds to the target … as a key fits a lock. The better
the fit the more likely it is that the compound will remain in place
and have an effect on the cell.
olden days, anti-cancer drugs were identified by trial and error –
by screening to see which compounds showed signals of activity in
various (and very imperfect) cancer cell models. Nowadays, the
target is identified first, the compound is then designed (shaped)
to bind to the target. For this reason we can anticipate an
improved chance of benefiting from participating in phase I cancer
trials – depending on the importance of the target.
drug development, the specificity of the drug to the target
is also important. Does the target also exist in heart or lung
cells? Cell culture and even animal models can’t tell us about this
… reliably. Compounds with the high specificity will bind only to a
portion of the tumor cells. Compounds with low specificity will
have many off-target effects … leading to more side effects.
the compound be safe to administer when given at a biologically
active dose? A Paracelsus noted, “The right dose differentiates a
poison and a remedy." Table salt is a poison at high doses.
Compounds found in seasoning may well be toxic if given at high
doses or in new ways that allow the compound to reach the blood at
safety record for phase I trials is very good because of the extra
steps to monitor for patient safety. The patient is followed
carefully by monitoring factors in the blood – such as elevated
kidney and liver enzymes. The dose is increased slowly – sometimes
in the same patient (intra-patient dose escalation) or in different
groups (dose cohorts). For each participant, blood samples are
taken often to check for signals of toxicity and also to carry out pharmacokinetic
studies to learn how the compound behaves in the body.
Pharmacokinetics (PK) is a core part of legitimate cancer
drug study (and is notably missing in Internet claims for the
therapeutic use of herbs). PK is defined as the study of the time
course of drug Absorption, Distribution, Metabolism, and Excretion (ADME).
The PK studies help to identify a dose and schedule for next phase
of clinical studies – a dose that has a scientifically plausible
potential to have therapeutic effects with acceptable toxicity (a
dose identified in phase I studies is sometimes the maximum
tolerated dose (frequently abbreviated as the MDT). The range of
doses that’s found to be active and safe is sometimes called the
therapeutic window. The width of the window is sometimes
called the therapeutic index. A compound with a narrow therapeutic
window will require more caution when administered in part because
compounds can behave differently in different people - may clear
faster or slower in me than in you, for example.
(where cancer cells are implanted in a mouse or other animal)
may be used to estimate a safe starting dose for a compound when
it’s first tested in humans.
Anti-cancer activity in test tube experiment may
be based on constant exposure to high concentrations of the
compound and therefore cannot account for the AMED of PK (how
the compound behaves in the body of a person at other
Cancer cells are very difficult to keep alive in
a test tube even under the most favorable conditions. It seems
that normal bystander cells are needed to keep lymphoma cells
alive. This is a major barrier to making more rapid progress
The cancer cell lines used in preclinical research are also very
different than the cancer cells that arise in people.
The overwhelming majority of compounds showing
activity in test tube experiments do not pan out – are
ineffective or too toxic at the biologically active dose.
For compounds taken by mouth, absorption varies a
lot. For example, very little of the herbal compound curcumin
is absorbed into the blood when taken orally. For this reason
nano particle delivery is being explored as a way to administer
compounds with poor bioavailability. Will the compound be safe
when delivered in high doses into the blood in this way? What
will be the off-target effects? The delivery method can change
the safety profile substantially.
made by animal,
plant, or by man: the molecular structures of the compounds are
Being “natural” does not increase the potential for safety or
efficacy– it merely describes the source. Natural compounds
made by plants and animals can be as deadly as man-made
Compounds (from any source) that do not have side effects, are
very unlikely to have treatment effects either.
Buyer beware that herbal products are not
regulated by FDA for purity and may have undeclared additives
and contaminants. The dose on the label is often wrong.
Search for ConsumerLabs for details.
In theory, compounds (from any source) given at
low but biologically active doses can foster treatment
resistance. The low or intermittent exposure to the compound
allowing the cells to adapt to develop resistance pathways.
Presumably, this is the reason that research focuses on finding
the highest tolerated dose of a new compound … and that
protocols usually involve combinations of agents that work by
different mechanisms of action.