Thermochemical Ablation - Physics of Thermal Therapy - page 338

any therapy. Lacking a replacement liver, there is a survival ceil-
ing, as it were, beyond which there is no additional benefit.
To place thermochemical ablation in context, it is helpful to
briefly review a number of existing or developing options. These
include chemical ablation, 7, 8 thermal ablation (hot or cold), 9-11
external beam radiation, and, most recently, high intensity focused
ultrasound (HIFU, in simplest terms another form of thermal
ablation), 12-14 and irreversible electroporation. The transarterial
therapies such as bland embolization, chemoembolization, and
radioembolization are outside the scope of this discussion. It is
worth noting, however, that there is a recognized survival benefit
in appropriately chosen patients for chemoembolization on the
order of 1-2 additional years of life and in many cases more.
Historically, chemical ablation is the oldest method for practical
purposes and is performed by instillation of 95-100% ethyl alco-
hol into tumors under ultrasound or CT guidance using a sidehole
needle. 15 The tumoricidal effect of this treatment has been attrib-
uted to dehydration and denaturation of the cells and proteins.
Mechanistically, these are ideas are intertwined and to some extent
redundant as protein structure is intimately related to the hydra-
tion state. The other chemical agent that has been used, although
less widely accepted, is 50% acetic acid. 16, 17 It is thought to work
in a similar manner, but adding a pH change that is assumed to
play a role in the denaturation. Since it penetrates and solvates col-
lagen better than ethanol, it is thought to do a better job than etha-
nol diffusing throughout tumor septae. This theoretically should
allow better treatment of small satellite nodules that are not grossly
apparent on imaging, leading to less local recurrence.
There are two main issues with these agents. One, inherent to all
injectable therapies, is distribution of these agents that tracks along
paths of least resistance. This can lead to injury to nearby structures
and incomplete treatment, even in encapsulated tumors. The other is
the intrinsic systemic toxicity resulting from exposure to either agent.
Ethanol toxicity can manifest as CNS depression, respiratory depres-
sion, pulmonary hypertension, and cardiovascular collapse. 18-21 Less
is known about acetic acid, but renal toxicity from hemolysis has
been reported. 22 In either case, multiple sessions treating with small
volumes has been the rule. To address the distribution issue, a multi-
tine, multi-sidehole needle has been developed. Published reports
show promising results, but it has not been widely adopted. 23-25
Both of these issues are addressed by the thermal methods, but
they too have limitations. Cryoablation has been reported but in
the liver has not been as widely accepted as the hyperthermic meth-
ods, mainly radiofrequency (RF) and microwave (MW) ablation.
Mechanistically, again hyperthermic protein denaturation has been
invoked as the predominant mechanism of action and is described
in detail elsewhere in this volume. The predictability of shape of the
resulting coagulum or devitalized zone and injury to nearby tissues
are the main problems for RF and MW ablation. The presence of
larger blood vessels acting as heat sinks and even the perfusion-
mediated cooling of tissues at the capillary level can lead to residual
viable tumor and local recurrence. Assuming the area is completely
treated, an advantage over chemical ablation is that lesions can gen-
erally be treated in one session. Commonly, these procedures are
done under general anesthesia, which adds to both the risk and the

cost. Economic situations are highly variable, but in general capital
budgeting is required for power generators for RF and MW tech-
nology, and the single-use probes are somewhat costly.
The situation as outlined herein presented an opportunity to ask
if it were possible to improve on chemical ablation in some way.
Since the dose-limiting issue is systemic toxicity, this was a logical
avenue to pursue. Initially, efforts were focused on decreasing the
acid load by neutralization after the fact, which is to say injection
of a base to neutralize the acid within the tissues. This poses at least
two problems, however. One is how to ensure that the base would
come in contact with the acid, and the other is what would happen
if base does not come in contact with acid. This incomplete reac-
tion would lead to treating other areas with base, systemic expo-
sure to excess base, or most likely some degree of both problems
could occur. It would be possible, if base were to react with the acid,
though, for heat to be evolved. Thus was born the initial concept
for thermochemical ablation. This was subsequently shown in our
lab (unpublished results) and others to occur in tissues. 26 However,
for the reasons outlined here, it did not appear to be a viable strat-
egy. The concept then evolved, and the question of how to proceed
became essentially inverted. That is to say, if the sole emphasis was
on releasing heat in the tissues, how much would be available?
To answer this question, at least three general variables must be
considered. First, what kind of tissue is under consideration? In
other words, what is the specific heat of the target tissue? Second,
how high of a temperature elevation is targeted and for how long?
This equates to the traditional question of the target thermal dose.
Finally, what kind of chemistry might be applied to the problem?
Using an exotherm as the sole criterion leaves open far too many
possibilities.
The first question can be dealt with in a straightforward fash-
ion. For liver cancer, liver tissue, and liver tumor a specific heat
of 3.6 kJ/kg-K has some basis in the literature. 27-29 This allows
one to actually calculate requirements if a certain size tumor, 3
cm for example, is heated to 55°C, a temperature at or near which
devitalization is nearly instantaneous. Allowing for a 1 cm mar-
gin, and for the moment ignoring any perfusion-mediated cool-
ing factors, a sphere of 5 cm in diameter would have a volume of
approximately 67 mL. Thus to heat such a volume of tissue from
a body temperature of 37°C to 55°C, the change in temperature
is 18°C. Assuming a time frame ranging from 1 sec to 100 sec,
the energy input requirement to raise this volume of tissue by
18°C is 4-400 W. This calculation provided a target range for
feasibility considerations for any particular chemistry.
The reaction of an acid and base was mentioned previously as
an example of exothermic chemistry. The molar heat of formation
for water, which is one of the products of acid-base neutralization,
is 55 kJ/mole with a common example shown in Figure 19.1.

HC1 + NaOH NaC1 + H 2 O + Heat

FIGURE 19.1 Neutralization reaction of hydrochloric acid with
sodium hydroxide to produce common table salt and water. The reac-
tion also releases a substantial amount of energy on a per mole basis.
Note that energy is not produced per se.