Testing a Cure for Hepatocellular Carcinoma

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Analyzing the use of lyso-thermosensitive liposomal doxorubicin

Hepatocellular carcinoma (HCC) is mainly diagnosed in patients with hepatic disease and cirrhosis, typically hepatitis C in the United States and Europe and hepatitis B in Asia. HCC is the second-leading cause of cancer deaths worldwide.

HCC lesions with a maximum diameter of<3cm are curable by surgery, liver transplantation, or radiofrequency ablation (RFA). RFA is guided by ultrasound or by computerized tomography and has been used safely in lesions up to 7cm. For >3cm tumors, the likelihood of cure is much reduced. For such larger lesions, multiple overlapping ablation cycles are required to ablate the tumor plus a 360° 1-cm margin.

When multiple ablations are performed in large tumors, RFA is more likely to leave viable tumor cells in the margins of overlapping ablation zones. This increases the possibility of rapid recurrence at the original site as well as elsewhere, due to vascular spread. The RFA literature recommends a minimum of four ablation cycles to ablate a >3.0cm tumor together with its 360° 1.0-cm margin. In our experience, it takes >45 minutes to administer four ablation cycles.

Lyso-thermosensitive liposomal doxorubicin (LTLD, ThermoDox) was designed for use with RFA as a curative treatment for 3-7cm HCC. It consists of the heat-enhanced cytotoxic doxorubicin within a heat-activated liposome. Doxorubicin monotherapy has long been used as a palliative treatment for HCC. A review of 13 published trials of single-agent doxorubicin among 644 HCC patients found a 19% objective response rate.

LTLD is administered by intravenous infusion. The liposomes selectively localize within and around tumor tissues because of their heightened permeability and retention properties. At normal body temperatures, doxorubicin remains encapsulated within the liposomes. LTLD is engineered to release its doxorubicin within seconds of reaching >40°C. The anticancer drug then quickly diffuses into the local tissue. Heated LTLD produces doxorubicin tumor concentrations up to 25-fold greater than free (non-liposomal) doxorubicin administered at the same doses. Doxorubicin is heat-enhanced in that in vitro studies show increased cell killing when combined with hyperthermia compared to the same dose of doxorubicin without hyperthermia.

With the RFA + ThermoDox combination, HCC patients should benefit from heat in three ways: ablating the visible tumor, generating a very high doxorubicin concentration in the heated target area, and increasing the antitumor activity of doxorubicin. Consistent with its heat-based mechanism of action, three preclinical studies found that duration of heating is the key to LTLD activity.

A computational modelling study investigated doxorubicin concentration in liver tumor tissue following combination therapy with LTLD and hyperthermia. This simulation combined a heat transfer model based on the bioheat equation with a drug delivery model. It simulated five hours of 43°C hyperthermia beginning 15 minutes after completing a 15-minute LTLD infusion. Maximum doxorubicin tumor tissue concentration was reached after 120 minutes of mild hyperthermia. This model found a direct correlation between duration of hyperthermia and doxorubicin concentration in tumor tissue, with 75% of the doxorubicin delivered in the first 45 minutes of heat and 25% of the doxorubicin delivery occurring in the next 75 minutes of applied heat.

Another computational modelling study of RFA and LTLD used a coupled heat-transfer and electric DC model to simulate RFA heating and the bioheat transfer equation to simulate tissue perfusion. These researchers found that the amount of bioavailable doxorubicin in the tumor margin increases as RFA heating time increases from five to 60 minutes. About 89% of the total doxorubicin concentration had been achieved by 45 minutes.

A study of RFA + LTLD in healthy pigs evaluated duration of RFA on doxorubicin target tissue concentration. Three heating times were tested: 15, 45, and 90 minutes. The study was conducted in pigs because they have perfused livers that are similar in size to the human liver, which allows use of clinically relevant radiofrequency generators and ablation probes. Overall, the pig data show an increase in both the amount of doxorubicin deposited and the width of the tumor margin to which doxorubicin is delivered when heat time is increased from 15 to 45 minutes, with minimal further increase over the next 45 minutes. Furthermore, fluorescence imaging shows that a high concentration of doxorubicin is found in the margin of the ablation zone and in areas where the ablations overlap, supporting the hypothesis that LTLD addresses any microscopic tumors left behind in the clefts of overlapping ablations. This result was observed with both of the commercially available RFA devices used and was supported both by tissue extraction and assay and by fluorescent imaging. Both RFA devices showed a focused delivery of high concentrations of doxorubicin to the tumor margin.

In a Phase I liver cancer trial, the maximum tolerated dose of LTLD was found to be 50mg/m2. The safety profile of LTLD was similar to that of free doxorubicin. Reversible neutropenia was the main toxicity. Unlike with a pegylated formulation of liposomal doxorubicin, no hand-foot syndrome was seen. About 90% of the liposomal doxorubicin plasma AUC0-∞ occurs during the first three hours following infusion, establishing this period as optimal for RFA. The study found a LTLD dose-response relationship for time to treatment failure (P = 0.04).

The preclinical data seem to suggest that RFA dwell time should be at least 45 minutes. RFA dwell time is the time from first turning on the RFA device to turning it off for the last time, including all ablations performed. Dwell time is relevant for LTLD activity because the target tissue and its surroundings remain at ≥ 40.0°C between ablation cycles.


References

  1. Gasselhuber A, Dreher MR, Partanen A, et al. Targeted drug delivery by high intensity focused ultrasound mediated hyperthermia combined with temperature-sensitive liposomes: computational modelling and preliminary in vivo validation. Int J Hyperthermia. 2012;28:337-48.
  2. Poon RT, Borys N. Lyso-thermosensitive liposomal doxorubicin: an adjuvant to increase the cure rate of radiofrequency ablation in liver cancer. Future Oncol 2011;7:937-45. Available at: http://celsion.com/files/082011.pdf
  3. Study of ThermoDox With Standardized Radiofrequency Ablation (RFA) for Treatment of Hepatocellular Carcinoma (HCC) (OPTIMA). Available at: https://clinicaltrials.gov/ct2/show/NCT02112656?spons=Celsion&rank=2
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About Author

Nicholas Borys, MD

Senior vice president and chief medical officer of Celsion.

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