The HALT study aims to evaluate histotripsy in an Asian population for both primary (HCC, CCA) and secondary liver malignancies with liver-limited or oligoprogressive disease. In addition to safety and local control, the study incorporates translational endpoints including immune profiling (PBMCs, cytokines), microbiome shifts, and optional tumour biopsies. This trial will provide critical data on the feasibility, tolerability, and biological impact of histotripsy in a region with the highest burden of liver cancer.

This will be a single-arm, multi-centre, prospective pilot study enrolling patients with:

A) Liver limited malignancies (primary or secondary) not eligible for/declined resection or other locoregional treatment modalities.

B) All solid cancer patients (e.g., HCC, colorectal, breast, pancreatic cancers etc) undergoing systemic therapy with oligoprogressive liver disease (defined as ≤ 3 liver limited progressive lesions, ≤ 3 cm in maximum diameter having received > 3 months of systemic therapy).

Patients will undergo baseline imaging and laboratory investigations, followed by histotripsy treatment under general anaesthesia. Post-procedure assessments will be performed at predefined intervals for clinical, radiologic, and biomarker evaluation.

Inclusion Criteria:

1. Age ≥21 years at the time of consent.

2. Histologically/cytologically confirmed cancers (imaging diagnosis as per AASLD allowed for HCC):

   A) Liver limited malignancies (primary or secondary) not eligible for/declined resection or other locoregional treatment modalities.

   B) All solid cancer patients (e.g., HCC, colorectal, breast, pancreatic cancers etc) undergoing systemic therapy with oligoprogressive liver disease (defined as ≤ 3 liver limited progressive lesions, ≤ 3 cm in maximum diameter having received > 3 months of systemic therapy).

3. Characteristics of hepatic lesions intended for treatment:

   • Up to 3 hepatic lesions.
   • Tumour ≤ 3 cm in longest diameter.
   • Lesion(s) must be visible and targetable by ultrasound.

4. ECOG Performance Status 0-1.

5. Child-Pugh class A or B7 liver function for patients with underlying cirrhosis.

6. Adequate hematologic and organ function within 14 days prior to treatment:

   • Haemoglobin ≥ 9.0 g/dL
   • Platelets ≥ 75,000/mm³
   • INR ≤ 1.5 × ULN
   • Estimated (by Cockroft-Gault or Modification of Diet in Renal Disease (MDRD) or measured creatinine clearance ≥ 50ml/min.
   • Total bilirubin ≤ 1.5 × upper limit normal or direct bilirubin ≤ ULN for participants with total bilirubin > 1.5 × ULN (participants with known history of elevated indirect bilirubin level suggestive of extrahepatic source of elevation e.g. Gilbert's disease may be recruited with bilirubin levels ≤ 3 × ULN)
   • AST and ALT ≤ 5 × ULN

7. Ability to undergo general anaesthesia, as confirmed by pre-anaesthetic assessment.

8. Life expectancy ≥ 3 months in the opinion of the investigator.

9. Willing and able to comply with study visits and procedures.

10. Written informed consent obtained prior to any study-related procedures.

Exclusion Criteria:

1. Extrahepatic disease progression requiring immediate systemic intervention, including new brain metastases or malignant ascites.

2. Vascular invasion, defined as gross involvement or encasement of major portal vein or hepatic vein branches.

3. Tumours located adjacent (<5 mm) to hollow viscera (e.g., stomach, colon) where histotripsy poses perforation risk.

4. Lesions poorly visualized on ultrasound or not targetable due to overlying ribs or gas.

5. Severe or uncontrolled comorbidities including:

   • Uncontrolled hypertension or cardiovascular disease
   • Active infection (requiring systemic therapy)
   • Severe chronic obstructive pulmonary disease or hypoxia

6. Contraindications to general anaesthesia or surgery.

7. Pregnancy or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days prior to treatment.

8. Participation in another interventional trial within 4 weeks prior to enrollment, or concurrent participation in a therapeutic study.

9. Any condition that, in the investigator's judgment, may compromise the patient's safety or interfere with protocol adherence.

Patients will undergo baseline imaging and laboratory investigations, followed by histotripsy treatment under general anaesthesia.