Biomedical Engineering Reference
In-Depth Information
superficial hyperthermia devices, whereas the liver cancer
patients were treated with thermal ablation. Results of the chest
wall recurrence trial have not been published, nor has a full
report been published for the liver cancer trials. One limited
report has been published from the phase I liver trial, however
(Poon and Borys 2009). A description of the clinical rationale
and limited results for the liver trial follow.
10
1
y = 5E-15e
0.8844x
R
2
= 0.9066
16.8.2.1 primary Hepatocellular Carcinoma
Primary liver cancer is the third leading cause of cancer deaths
worldwide. Statistics from 2007 showed that there were over
700,000 cases and nearly as many deaths (680,000) (Sung and
Thung 2010). There is high incidence in Eastern Asia, such as
China and Japan, and the African Congo, but relatively low inci-
dence in the Western world. It is associated with transmission of
hepatitis B and C viruses. However, the most common risk factor
is cirrhosis, where it is thought that inflammation and prolifera-
tion likely play a role in its development. The difference between
the incidence and death rate clearly indicates that there is cur-
rently not an effective therapy for this disease. Less than 20% of
patients are suitable candidates for surgical resection, but when
successful, the five year survival rate is over 75%. Hepatic reserve
is an important consideration in the treatment of this disease,
which has led to the concept of localized therapies, such as ethanol
ablation, cryoblation, chemoembolization, and RF ablation.
LTSL-Dox has been tested as an adjuvant to thermal ablation
for medium (3.1-5 cm) and large (>5 cm) tumors in seriously
impaired livers. The rationale for this approach is to widen
the margin of the ablation zone, to kill tumor cells that have
invaded adjacent normal liver, and/or to increase the treatment
margin in regions of thermally significant vessels where tem-
peratures fall below that required for thermal ablation. RFA
has been a successful treatment for small lesions in this dis-
ease. Local recurrences have been reported to be less than 20%
for lesions <3 cm, but the local failure rate is higher for larger
lesions.
A phase I trial was conducted in 24 patients who received RF
ablation for hepatocellular carcinoma or metastatic liver cancer
(Poon and Borys 2009). he MTD was 50 mg/M
2
. he phar-
macokinetics of the drug are similar to what was observed in
the canine trial, with most of the doxorubicin exposure occur-
ring in the 6 hr after the end of drug infusion (Figure 16.9).
The dose-limiting toxicities were grade 3 alanine aminotrans-
ferase increase and grade 4 neutropenia, which were observed
at a dose of 60mg/M
2
. Half of the tumors treated in this trial
were between 3.8 and 6.5 cm in diameter. There was a statis-
tically significant dose effect. The median time to failure for
patients who received less than the MTD was 80 days, whereas
for those who received the MTD dose, it was 374 days (
p
=
0.0380). These results strongly suggest that LTSL-Dox has the
capacity to augment RF ablation. Based on this result, a phase
III multi-institutional randomized trial was opened by Celsion
Corporation in 2008 (Phase 3 Study of ThermoDox With
Radiofrequency Ablation (RFA) in Treatment of Hepatocellular
Carcinoma (HCC); NCT00617981). The trial is currently open,
0.1
35.5
36
Mean body temp (ºC) from end of IV to 1 hr post infusion
36.5
37
37.5
38
38.5
39
FIGURE 16.8
Doxorubicin plasma clearance vs. mean deep rectal
(systemic) temperature at end of heating period in tumor-bearing dogs
treated in a phase I trial of LTSL-Dox + HT. The range of temperatures
is below that required for LTSL drug release. Thus, the change in clear-
ance rate is likely a reflection of the treatment volume vs. body weight
size of the animals being treated. When the treatment volume is large
relative to body size, then more drug is released in the heated volume,
leading to an elevated clearance rate. It is possible that free drug is being
released intravascularly in the heated volume as well, which would
increase the clearance rate. (Reproduced from Hauck, M. L. et al.,
Clin
Cancer Res
, 12, 2006. With permission.)
The terminal half-life of doxorubicin was 1.6 hr in this study.
Importantly, the doxorubicin clearance (L/hr) was found to be
linearly related to the rectal temperature at the end of the heat-
ing period in these animals (Figure 16.8). The rectal temperatures
were below that required for triggered drug release. This result
was likely associated with treatment volume. Larger tumor vol-
umes were more likely to result in relatively more systemic drug
release as a result of the local heating. It has been theoretically
estimated recently that the transit time of an LTSL through a
3 cm tumor may be <5 s (Gasselhuber et al. 2010). If this is the
case, some liposomes may escape the heated tumor region, since
the drug release time of LTSL is on the order of 10-20 s. If they
remain intravascular, they may dump drug outside the heated
volume. If this is the case, then one might expect to see free drug
in plasma during and after heating at a level higher than would
be expected after LTSL-Dox administration without heating. The
formulation does exhibit slow release at 37°C. As will be shown
later, free drug is measurable in the plasma of humans treated
with LTSL-Dox in the context of thermal ablation for liver cancer.
The tumors treated in this canine trial were relatively large
(median of 91 cm
3
), but of the 20 evaluable animals that received
at least two courses of chemotherapy, two experienced progres-
sion, 12 had stable disease, and the remaining six demonstrated
partial responses to the treatment.
16.8.2 Human trials
Phase I trials have been completed in patients with chest wall
recurrences of breast cancer and in patients with either pri-
mary or metastatic liver cancer. The former were treated with
