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Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial

  • Hepatobiliary-Pancreas
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objectives

Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB.

Methods

Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events.

Results

Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups.

Conclusions

The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events.

Trial registration

ChineseClinicalTrials.gov ChiCTR2100044721

Clinical relevance statement

This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events.

Key Points

• This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent.

• Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months.

• The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

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Abbreviations

2-D:

Two-dimensional

3D:

Three-dimensional

AIMS:

Acoustic intensity measurement system

CR:

Complete response

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events

DCR:

Disease control rate

DUS:

Diagnostic ultrasound

ECOG:

Eastern Cooperative Oncology Group

FDA:

Food and Drug Administration

HIFU:

High-intensity focused ultrasound

IEC:

International Electrotechnical Commission

IRE:

Irreversible electroporation

IV:

Intravenously

MB:

Microbubble

MI:

Mechanical index

OS:

Overall survival

PD:

Progressive disease

PDAC:

Pancreatic ductal adenocarcinoma

PET:

Positron emission tomography

PFS:

Progression-free survival

PL:

Pulse burst length

PNP:

Peak negative pressure

PR:

Partial response

PRF:

Pulse repetition frequency

RECIST:

Response Evaluation Criteria in Solid Tumours

RFA:

Radiofrequency ablation

ROI:

Region of interest

SD:

Stable disease

TUS:

Therapeutic ultrasound

US:

Ultrasound

USMBSs:

US-stimulated microbubbles

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Acknowledgements

We thank all the patients and their families who participated in the study; the doctors, nurses, pathologists, and other members of the multidisciplinary teams; and the research teams from the participating centres.

Funding

This study was funded by the National Key R&D Program of China (grant number 2017YFC0107300 to ZL), National Natural Science Foundation of China (grant number 82127804 to ZL, 82102075 to XD, 82102077 to NL), Chongqing Talent Project (to ZL), and Chongqing Chief Expert Program in Medicine (to ZL).

Author information

Author notes

  1. Feng Han, Yanjie Wang, and Xiaoxiao Dong are co-first authors and contributed equally to this work.

  2. Kun Yan, Anhua Li, and Zheng Liu are co-senior authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, 651 Dongfengdong Road, Guangzhou, 510060, China

    Feng Han, Qingguang Lin, Miao Yun & Anhua Li

  2. Department of Ultrasound, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 of Fucheng Road, Haidian District, Beijing, 100142, China

    Yanjie Wang, Yixi Wang & Kun Yan

  3. Department of Ultrasound, Xinqiao Hospital, Army Medical University, Chongqing, China

    Xiaoxiao Dong, Ningshan Li, Tingting Luo & Zheng Liu

  4. Department of Ultrasound, General Hospital of Central Theater, Wuhan, China

    Wenhong Gao & Shunji Gao

  5. Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China

    Yan Li

  6. Department of Ultrasound, Guangdong Second Provincial General Hospital, Guangzhou, China

    Huilong Huang

  7. Department of Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China

    Xiao Luo

  8. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China

    Miaozhen Qiu & Dongsheng Zhang

Authors
  1. Feng Han
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  2. Yanjie Wang
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  8. Yan Li
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  16. Kun Yan
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  18. Zheng Liu
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Corresponding authors

Correspondence to Kun Yan, Anhua Li or Zheng Liu.

Ethics declarations

Guarantor

The scientific guarantor of this publication is Zheng Liu.

Conflict of interest

The authors have declared that no conflicts of interest exist.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

The research protocol was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center (C2018-004-01) and the Institutional Review Board of Peking University Cancer Hospital & Institute (2018KT69).

Study subjects or cohorts overlap

None.

Methodology

  • Prospective

  • Randomised controlled trial

  • Multicentre study

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Han, F., Wang, Y., Dong, X. et al. Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial. Eur Radiol 34, 1481–1492 (2024). https://doi.org/10.1007/s00330-023-10210-4

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  • DOI: https://doi.org/10.1007/s00330-023-10210-4

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