Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin

Clinical question
Does burn time per tumor volume (BPV) in radiofrequency (RF) ablation and lyso-thermosensitive liposomal doxorubicin (LTLD) combination therapy for solitary hepatocellular carcinoma (HCC) correlate with treatment outcomes?

Takeaway point
Overall survival (OS) benefits were correlated with higher BPV in the RF ablation + LTLD combination compared to RF ablation alone in this retrospective post hoc analysis.

Reference
Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin, Volume 30, Issue 12, 1908-1914.

Click here for abstract

Study design
Post hoc analysis of the double-blind, randomized controlled phase III HEAT study of RF ablation only versus RF ablation + LTLD in patients with HCCs 3-7 cm in diameter.

Funding Source
Intramural Research Program of the National Institutes of Health and the National Institutes of Health Center for Interventional Oncology (grants ZID# BC011242-9 and CL040015-9). The National Institutes of Health has a Cooperative Research and Development Agreement with Celsion Corporation (Lawrenceville, New Jersey).

Setting
NIH, United States of America.






Figure 2. Hazard ratio versus BPV cutoff. As patients with smaller values of BPV were excluded, the hazard ratio decreased, representing improved benefit for patients receiving RF ablation + LTLD compared with patients receiving RF ablation only. When patients with < 2 min/mL BPV were excluded, the hazard ratio was 0.7, which meant survival of patients receiving RF ablation + LTLD improved 42.8% compared with patients receiving RF ablation only. With exclusion of patients with < 3.4 min/mL BPV, the hazard ratio and survival improvement for patients receiving RF ablation + LTLD became 0.5 and 100%, respectively, compared with patients receiving RF ablation only.

Summary

Radiofrequency (RF) ablation, despite its widely adopted and successful treatment of hepatocellular carcinoma (HCC), has limited results for tumors > 3 cm. Alternative treatment methods, such as the synergistic combination of RF ablation and lyso-thermosensitive liposoam ldoxorubicin (LTLD), are in development. Although the phase III HEAT study did not demonstrate significant difference in progression-free survival (PFS) and overall survival (OS) between RF ablation only and RF ablation + LTLD, initial post hoc subgroup analysis in patients with > 45 minutes dwell time demonstrated improved OS of patients receiving RF ablation + LTLD compared to RF ablation only. Based on the LTLD formulation and pharmacokinetic modeling, it was hypothesized that RF ablation duration with respect to tumor volume would contribute significantly to treatment outcomes of RF ablation + LTLD in HCC.

HEAT study data was analyzed retrospectively. Original data was a double-blind, randomized controlled study with 701 patients of HCC between 3 cm and 7 cm distributed between RF ablation only and RF ablation + LTLD. Only patients with solitary tumors were further analyzed (n = 210 patients who received RF ablation only; n=227 patients who received RF ablation + LTLD). Hazard ratios were calculated with incremental threshold values of BPV. A univariate and multivariate Cox proportional hazard model was used for analysis.

No significant difference was found in terms of tumor volume, average burn times, or BPVs between the two treatment arms. Multiple covariate Cox survival analysis demonstrated BPV as a significant effect modifier, with each 1 min/mL increase in BPV contributing to an increase of 17.6% in overall survival in the RF ablation + LTLD arm compared to RF ablation alone. Univariate Cox survival analysis with incremental BPV cutoff values demonstrated gradually decreasing hazard ratios, signifying more pronounced effects of BPV on OS with higher threshold of BPV. Independently performed univariate Cox analysis within each treatment arm confirmed significant effects of BPV on OS in the RF ablation + LTLD arm; but not on PFS, nor in the RF ablation only arm. Feasibility analysis demonstrated that almost 80% of all examined solitary tumors could have been treated with a BPV of 2 min/mL if available burn time was 100 minutes.

Commentary

The authors in this study have demonstrated a potentially significant effect of BPV on the treatment outcomes of RF ablation + LTLD in solitary HCC between 3 cm and 7 cm through a post hoc analysis of the phase III HEAT study data. Results suggested a critical role of adequate burn time in RF ablation + LTLD treatment and BPV as a normalization/stratification metric. This study has its limitations given its retrospective post hoc nature as ablation time and other important variables were not included in the original analysis plan. HCCs with significant tumor volumes (7 cm tumor would equate to an ablation time of 360 minutes with a BPV of 2 min/mL) were likely receiving disproportionately lower BPVs. Therefore, the effects of higher BPVs on overall survival could not be safely separated from the inherent survival benefit of having a smaller HCC. However, the call for a more standardized determination of RF ablation time, especially in the RF ablation + LTLD combination regimen given its preclinical mechanistic data, should not be understated. Future prospective studies should be conducted to further evaluate the effects of ablation time in RF ablation + LTLD treatment for HCC and the potential of using BPV as a standardization metric.


Post author
Ningcheng (Peter) Li, MD, MS
Integrated Interventional Radiology Resident, PGY-3
Department of Interventional Radiology
Oregon Health and Science University, Dotter Interventional Institute
@NingchengLi