Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions

Won Young Tak, Shi Ming Lin, Yijun Wang, Jiasheng Zheng, Aldo Vecchione, Soo Young Park, Min Hua Chen, Stephen Wong, Ruocai Xu, Cheng Yuan Peng, Yi You Chiou, Guan Tarn Huang, Jianqiang Cai, Basri Johan Jeet Abdullah, June Sung Lee, Jae Young Lee, Jong Young Choi, Julieta Gopez-Cervantes, Morris Sherman, Richard S. FinnMasao Omata, Michael O'Neal, Lukas Makris, Nicholas Borys, Ronnie Poon, Riccardo Lencioni

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Abstract

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-totreat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes.

Original languageEnglish (US)
Pages (from-to)73-83
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2018

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Hepatocellular Carcinoma
Doxorubicin
Disease-Free Survival
Survival
Confidence Intervals
Hot Temperature
liposomal doxorubicin
Liposomes
Research Design
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. / Tak, Won Young; Lin, Shi Ming; Wang, Yijun; Zheng, Jiasheng; Vecchione, Aldo; Park, Soo Young; Chen, Min Hua; Wong, Stephen; Xu, Ruocai; Peng, Cheng Yuan; Chiou, Yi You; Huang, Guan Tarn; Cai, Jianqiang; Abdullah, Basri Johan Jeet; Lee, June Sung; Lee, Jae Young; Choi, Jong Young; Gopez-Cervantes, Julieta; Sherman, Morris; Finn, Richard S.; Omata, Masao; O'Neal, Michael; Makris, Lukas; Borys, Nicholas; Poon, Ronnie; Lencioni, Riccardo.

In: Clinical Cancer Research, Vol. 24, No. 1, 01.01.2018, p. 73-83.

Research output: Contribution to journalArticle

Tak, WY, Lin, SM, Wang, Y, Zheng, J, Vecchione, A, Park, SY, Chen, MH, Wong, S, Xu, R, Peng, CY, Chiou, YY, Huang, GT, Cai, J, Abdullah, BJJ, Lee, JS, Lee, JY, Choi, JY, Gopez-Cervantes, J, Sherman, M, Finn, RS, Omata, M, O'Neal, M, Makris, L, Borys, N, Poon, R & Lencioni, R 2018, 'Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions', Clinical Cancer Research, vol. 24, no. 1, pp. 73-83. https://doi.org/10.1158/1078-0432.CCR-16-2433
Tak, Won Young ; Lin, Shi Ming ; Wang, Yijun ; Zheng, Jiasheng ; Vecchione, Aldo ; Park, Soo Young ; Chen, Min Hua ; Wong, Stephen ; Xu, Ruocai ; Peng, Cheng Yuan ; Chiou, Yi You ; Huang, Guan Tarn ; Cai, Jianqiang ; Abdullah, Basri Johan Jeet ; Lee, June Sung ; Lee, Jae Young ; Choi, Jong Young ; Gopez-Cervantes, Julieta ; Sherman, Morris ; Finn, Richard S. ; Omata, Masao ; O'Neal, Michael ; Makris, Lukas ; Borys, Nicholas ; Poon, Ronnie ; Lencioni, Riccardo. / Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 1. pp. 73-83.
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abstract = "Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-totreat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95{\%} confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95{\%} CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95{\%} CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes.",
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T1 - Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions

AU - Tak, Won Young

AU - Lin, Shi Ming

AU - Wang, Yijun

AU - Zheng, Jiasheng

AU - Vecchione, Aldo

AU - Park, Soo Young

AU - Chen, Min Hua

AU - Wong, Stephen

AU - Xu, Ruocai

AU - Peng, Cheng Yuan

AU - Chiou, Yi You

AU - Huang, Guan Tarn

AU - Cai, Jianqiang

AU - Abdullah, Basri Johan Jeet

AU - Lee, June Sung

AU - Lee, Jae Young

AU - Choi, Jong Young

AU - Gopez-Cervantes, Julieta

AU - Sherman, Morris

AU - Finn, Richard S.

AU - Omata, Masao

AU - O'Neal, Michael

AU - Makris, Lukas

AU - Borys, Nicholas

AU - Poon, Ronnie

AU - Lencioni, Riccardo

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-totreat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes.

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