The Role of High-Intensity Focused Ultrasound as a Local Consolidative Therapy in Multimodal Conversion Treatment for Colorectal Liver Metastases: A Case Series

Abstract

Introduction

This retrospective case series evaluated the feasibility, safety, and potential clinical role of high-intensity focused ultrasound (HIFU) as local consolidative therapy (LCT) in patients with initially unresectable colorectal liver metastases (CRLM).

Methods

We retrospectively reviewed five patients with CRLM between 2019-2023 who underwent HIFU ablation in addition to systemic chemotherapy. Tumor response was assessed by contrast-enhanced MRI using modified Response Evaluation Criteria in Solid Tumors (mRECIST). Adverse events, conversion to resectability, and survival outcomes were analyzed.

Results

All five patients underwent R0 resection after treatment incorporating systemic chemotherapy, HIFU, and surgery (median HIFU-to-surgery interval 383 days; range 17–1361 days), suggesting potential utility of HIFU both as immediate consolidation and as a long-term bridge-to-resection therapy. Only mild, self-limiting adverse events (transient liver enzyme (AST/ALT) elevation and local edema) were observed; no severe complications occurred. Median overall survival (OS) from diagnosis of liver metastases was 63.8 months, with 1-, 2-, 3-, and 5-year OS rates of 100%, 100%, 80%, and 60%, respectively. Median OS from the date of first HIFU treatment was 51.4 months (1-, 2-, 3-, and 5-year rates: 100%, 100%, 80%, and 60%).

Conclusions

HIFU appears to be a safe local ablative technique and may be integrated into multimodal management of initially unresectable CRLM, and may support conversion to curative-intent resection with encouraging survival outcomes in this small series. Larger prospective studies are warranted to validate these findings and define optimal patient selection and treatment sequencing.

Keywords

high-intensity focused ultrasound (HIFU)colorectal cancer liver metastases conversion therapy local ablation

1. Introduction

Colorectal liver metastases (CRLM) is a principal determinant of patient prognosis. Approximately 15%-25% of patients present with synchronous liver metastases at diagnosis,^1,2 while up to 50% will develop metachronous metastases following resection of the primary tumor.³ The metastatic cascade involves a complex interplay of tumor cell intrinsic changes, such as epithelial-mesenchymal transition (EMT)⁴ and activation of pathways such as the Wnt/β-catenin,⁵ and remodeling of the liver microenvironment into a receptive microenvironment (“soil”) through inflammatory mediators and hypoxia-induced angiogenesis.^6,7

Surgical resection remains the primary potentially curative modality for CRLM, yet only 20%-30% of patients are candidates at initial diagnosis.^8,9 Conversion therapy aims to render initially unresectable metastases resectable and is therefore a critical strategy. This often involves a combination of systemic chemotherapy, targeted agents, and local therapies.¹⁰ The integration of modern systemic and local treatments has increased conversion rates from 15%-40% to 47%-55% in contemporary series.^11-13

Among local therapies, ablation techniques and stereotactic body radiotherapy (SBRT) are options for nonsurgical candidates,^14,15 while hepatic artery infusion chemotherapy (HAIC) can achieve high local drug concentrations.⁹ However, challenges persist, including chemotherapy-associated toxicity, anatomical limitations for ablation, and high post-resection recurrence rates exceeding 60% at 5 years.^16-18 Minimal residual disease, often undetectable by conventional imaging, is a major source of recurrence.¹⁹ Furthermore, the poor response of microsatellite stable (MSS) CRLM to immunotherapy and intra-tumoral heterogeneity continue to limit treatment efficacy.²⁰

High-intensity focused ultrasound (HIFU) is a non-invasive technique that ablates tumor tissue via thermal effects (≥60 °C) induced by externally focused ultrasound energy.²¹ Beyond its direct cytotoxic effect, HIFU may simultaneously stimulate antitumor immunity. This case series evaluates the feasibility and preliminary safety of integrating HIFU into the conversion therapy paradigm for CRLM.

1.1. Literature Review: Local Treatment Strategies for Liver Metastases From Colorectal Cancer

The contemporary management of CRLM involves a multimodal treatment strategy, primarily comprising surgical resection, systemic chemotherapy, and radiation therapy, each presenting a unique profile of benefits and constraints. A central tenet of treatment is optimizing the balance between durable local control and preventing systemic disease progression.

1.1.1. Surgical Excision

Curative-intent resection with preservation of an adequate functional future liver remnant preservation constitutes the cornerstone of curative-intent treatment for CRLM, affording 5-year survival rates of 50%-60%.²² Technical refinements, such as parenchymal-sparing hepatectomy guided by intraoperative ultrasound, allow for precise tumor excision while conserving vascular integrity and mitigating the risk of postoperative hepatic insufficiency.²³ The adoption of laparoscopic approaches has further enhanced recovery outcomes.^24,25 Notwithstanding these advances, anatomical constraints, multifocal disease, and insufficient future liver remnant restrict surgical eligibility to only 20%-30% of patients at diagnosis.^8,9 Moreover, postoperative recurrence remains a formidable obstacle, with rates surpassing 60% within five years, often attributable to occult micrometastases.^16-18 Complications such as bile leakage and liver failure not only compromise recovery but may also negatively influence oncological outcomes, and their management remains a clinical challenge.^26,27

1.1.2. Liver Transplantation

For a highly selected subset of patients with unresectable liver-confined metastases, transplantation based on criteria such as those used in the SECA studies has yielded impressive 5-year survival rates up to 83%.²⁸ The TRANSMET randomized controlled trial further corroborated this potential, reporting a 5-year overall survival of 57% for transplantation combined with chemotherapy.²⁹ However, the application of transplantation in this setting is hampered by contentious eligibility criteria, a profound scarcity of donor organs, and the inherent complexities and long-term risks associated with lifelong immunosuppression.^30,31

1.1.3. Chemotherapy

Systemic chemotherapy, primarily utilizing FOLFOX (oxaliplatin, 5-FU/leucovorin) and FOLFIRI (irinotecan, 5-FU/leucovorin) regimens, forms the backbone of systemic treatment. The integration of targeted agents (e.g., bevacizumab, cetuximab) has enhanced response rates, enabling conversion to resection in 15%-40% of initially unresectable cases.^32-36 Hepatic arterial infusion chemotherapy (HAIC) capitalizes on the liver’s first-pass effect to achieve high regional drug exposure, which can prolong recurrence-free survival.³⁷ Despite its efficacy, chemotherapy is compromised by significant limitations: it can induce an immunosuppressive liver microenvironment by polarizing macrophages towards an M2 phenotype³⁸; tumor heterogeneity underlies variable responses and ultimate therapeutic failure³⁹; and specific agents like oxaliplatin and irinotecan are associated with distinct hepatotoxicities, including sinusoidal obstruction syndrome and chemotherapy-associated steatohepatitis.^40,41 The paucity of dendritic cells within metastatic lesions further attenuates the anti-tumor immune response, potentially limiting the efficacy of immunotherapies.⁴²

1.1.4. Radiotherapy

Stereotactic body radiation therapy (SBRT) provides high-precision, conformal dose delivery, achieving local control rates of 70%-90% for metastases and keep≤5 cm¹⁵. Similarly, Yttrium-90 (Y90) radioembolization has demonstrated disease control rates of 80-92% in unresectable settings.⁴³ The utility of radiotherapy, however, is circumscribed by dose-limiting toxicities in non-target liver tissue (e.g., radiation-induced liver disease) and suboptimal efficacy for larger tumor volumes.¹⁴

1.1.5. Radiofrequency Ablation

Percutaneous thermal ablation is a well-established minimally invasive local treatment option for patients with colorectal liver metastases. Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most commonly used thermal ablation modalities. Both techniques exert their antitumor effects through localized thermal injury. Theoretically, MWA provides more homogeneous heating, whereas RFA may achieve higher intratumoral temperatures and reduce the impact of the heat-sink effect.⁴⁴ However, in most published studies, patients treated with RFA are more likely to have unresectable disease. In addition, the presence of extrahepatic disease, a higher burden of comorbidities, and variations in RFA techniques are associated with less favorable clinicopathological characteristics than those observed in patients with resectable disease undergoing hepatectomy.⁴⁵

1.2. Research Progress on HIFU for Liver Tumors

Focused ultrasound ablation can act via thermal or mechanical mechanisms; thermal HIFU primarily relies on heat deposition, whereas histotripsy relies on cavitation-driven mechanical tissue fractionation. By extracorporeally concentrating ultrasonic energy onto a focal point within the target, it induces coagulative necrosis when sufficient thermal dose is achieved (often >60°C at the focus), constituting a truly noninvasive therapeutic modality.⁴⁶ Its clinical application has been reported across several conditions, including benign uterine fibroids and malignancies such as prostate, breast, hepatic, and pancreatic tumors. For instance, in primary liver cancer, the combination of HIFU with transarterial chemoembolization (TACE) has been associated with higher complete necrosis rates and improved 3-year survival compared with TACE alone monotherapy.⁴⁷

HIFU confers several safety advantages over conventional invasive techniques. As a non-invasive procedure, it avoids needle puncture–related risks (e.g., hemorrhage, tumor tract seeding).^48,49 Its precision allows for the safe ablation of lesions proximate to major vasculature, as flowing blood dissipates heat (heat-sink effect), preserving vascular integrity and potentially resulting in reduced bleeding and faster recovery in selected patients.⁵⁰ Beyond its direct ablative capacity, HIFU exhibits significant immunomodulatory potential. The mechanical destruction of tumor cells, particularly via non-thermal mechanisms in some HIFU modalities, may promote release of tumor antigens and could prime systemic antitumor responses.^51,52 Furthermore, unlike radiotherapy, HIFU is not constrained by ionizing radiation dose accumulation, allowing retreatment in some settings subject to anatomic and safety constraints.⁵³ Growing clinical evidence supports its application in liver tumors. The European multicenter HOPE4LIVER trial of histotripsy reported approximately 95% technical success/primary efficacy in destroying targeted tissue volumes.⁵⁴ Preclinical studies indicate that HIFU can remodel the tumor microenvironment towards an immunostimulatory phenotype, characterized by the infiltration and activation of dendritic cells, neutrophils, and B cells, thereby instigating both local and systemic inflammatory cascades against the tumor.⁵⁵ The THERESA feasibility trial further confirmed technical success, with post-ablation MRI at 24 hours showing regression in all treated tumors and an absence of serious adverse events within a 2-month follow-up period.⁵⁶ Most pertinently for CRLM, a comparative study demonstrated that combining HIFU with systemic therapy (FOLFOX/FOLFIRI ± targeted therapy) yielded superior objective response rates, median progression-free survival, and median overall survival compared to systemic therapy alone.⁵⁷ This synergy may be partly attributed to HIFU’s ability to disrupt the dense stromal barriers of metastases, thereby improving chemotherapeutic drug penetration. A Phase I trial involving 13 CRLM patients treated with ultrasound-guided HIFU employed a layered ablation strategy, achieving an objective response in all patients (ORR 100%), predominantly complete responses. However, intrahepatic recurrence occurred in 70% of patients, these lesions were often amenable to repeat HIFU sessions, underscoring its potential for iterative local control.⁵⁸ Finally, a prospective Phase I-IIa trial of intraoperative HIFU in 15 CRLM patients confirmed the feasibility, safety, and accuracy of the technique, with 13 patients completing treatment successfully and without damage to adjacent tissues.⁵⁹

2. Methods

2.1. Patient Selection

Between 2019 and 2023, five consecutive patients were included in this case series, all of whom had pathologically confirmed colorectal adenocarcinoma accompanied by synchronous or metachronous liver metastases. All patient details were de-identified prior to analysis and reporting to ensure that no individual could be identified. This study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (Approval No. QYFY WZLL 30817). Written informed consent was obtained from all participants prior to data collection. The consent covered the use of anonymized clinical data for research purposes and the publication of study findings. All procedures were conducted in accordance with the Declaration of Helsinki. The reporting of this study complies with the CARE guidelines.⁶⁰

2.1.1. Inclusion Criteria

1) Pathologically confirmed colorectal cancer (CRC) with liver metastases confirmed by imaging and/or pathology; either at initial presentation or after prior radical/palliative primary tumor surgery; 2) Liver metastases considered unresectable, or patients deemed medically inoperable, or patients who declined hepatic resection; 3) Aged 20–75 years, with an expected survival ≥3 months; 4) No functional failure of major systemic organs, liver function classified as Child-Pugh Grade A or B, and adequate cardiopulmonary function for anesthesia as assessed by pre-anesthesia evaluation; 5) Patients who can be followed up regularly in the outpatient department or during hospitalization; 6) No skin ulceration or severe scar hyperplasia in the acoustic pathway; 7) Patients undergoing high-intensity focused ultrasound (HIFU) treatment, with lesions clearly visualized using the integrated real-time ultrasound guidance system.

2.1.2. Exclusion Criteria

1) Patients with resectable disease or candidates for conversion therapy intended to achieve resectability who were fit for and willing to undergo surgery; 2) No pathological diagnosis; 3) Liver function classified as Child-Pugh Grade C; 4) Patients who cannot tolerate general anesthesia; 5) Comorbidity with systemic collagen diseases or autoimmune diseases.

2.2. Efficacy and Safety Evaluation

Treatment response was evaluated using the mRECIST criteria⁶¹ based on contrast-enhanced MRI performed one week after HIFU ablation. Technical efficacy (complete ablation) was defined as no residual contrast enhancement within the treated lesion on post-treatment imaging. All adverse events (AEs) and complications were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.⁶²

2.3. Preparation and Process of HIFU Treatment

The JC-type HIFU tumor therapy system (Chongqing Haifu Medical Technology) was used. Key parameters included a transducer frequency of 0.8 MHz, a power output range of 0-400 W, and a focal length of 15 cm. All patients underwent pre-procedural evaluation, including laboratory tests and contrast-enhanced abdominal MRI. Patient preparation involved a liquid diet and bowel cleansing, skin shaving and degreasing in the treatment area, placement of an indwelling urinary catheter, and, for subdiaphragmatic lesions, the creation of an artificial pleural effusion (hydrothorax) to improve the acoustic window (performed under ultrasound guidance when required).

HIFU was performed under general anesthesia. Patients were positioned to optimize the acoustic pathway. The integrated ultrasound probe was used for tumor localization and treatment planning. A computer-controlled protocol was executed to systematically ablate the target volume from deep to superficial layers. Sonication was delivered in a point-by-point manner with predefined stepwise coverage of the planned volume, under real-time ultrasound monitoring. Contrast-enhanced ultrasound was performed immediately post-ablation to confirm the non-perfused ablation zone.

2.4. Postoperative Management and Follow-Up

Patients were monitored for pain and skin changes. Systemic chemotherapy was withheld for 1 week before and 1 week after HIFU when feasible, and deviations were recorded. AEs were actively followed for 30 days post-procedure through inpatient monitoring, outpatient visits, and telephone follow-up.

3. Results

3.1. Clinical Characteristics Treatment Parameters

The cohort consisted of 4 males and 1 female, with a median age of 66 years (range: 55–73). Primary tumor sites were colon (n=4) and rectum (n=1). Liver metastases were synchronous in 3 and metachronous in 2 patients. The number of liver metastases per patient varied (1, 2, 4, 4, and five or more). Four patients received one HIFU session, while one required a second session. The maximum diameter of treated metastases ranged from 23–65 mm. Detailed patient characteristics and HIFU parameters are summarized in Table 1.

Table 1.

Clinical Characteristics of Patients From CRLM Treated With HIFU

Variable	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Sex	Male	Male	Male	Male	Female
Age (years)	73	64	66	55	59
ECOG PS	1	0	1	1	1
Previous lines of liver metastases therapy	FOLFIRI+ cetuximab→ hepatectomy	XELOX→ hepatectomy → FOLFIRI	FOLFOX→ hepatectomy + RFA	FOLFOX + cetuximab	Systemic therapy (details not specified)
Indication(s) for HIFU (code)	2, 3	2, 3	1	1	1
Tumor response after first HIFU	CR	CR	CR	PR	CR
Post-HIFU systemic/surgical treatments	Cape + cetuximab → FOLFIRI + cetuximab → FOLFOX + bevacizumab → hepatectomy → multiple subsequent lines	NA	Hepatectomy → XELOX → hepatectomy (after recurrence) → multiple subsequent lines	FOLFOX + cetuximab → cetuximab + cape (maintenance) → hepatectomy → multiple subsequent lines	Long-term maintenance → hepatectomy
Recurrence after first HIFU (site)	Hepatic	Hepatic	Hepatic	Hepatic	Hepatic
Time to recurrence after first HIFU (months)	4	8	14	14	45
Tumor response after second HIFU	NA	CR	NA	NA	NA

Reasons for HIFU treatment: 1. Palliative local treatment (for multiple tumor metastases, HIFU targets single or multiple local metastatic tumors); 2. Radical local treatment; 3. Patients rejected other local treatments, or these treatments were ineffective or intolerable.

Abbreviations: Cape, capecitabine; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, fluorouracil/leucovorin/irinotecan; FOLFOX, fluorouracil/leucovorin/oxaliplatin; HIFU, high-intensity focused ultrasound; NA, not applicable; PR, partial response; RFA, radiofrequency ablation; XELOX, capecitabine/oxaliplatin.

3.2. Timing of Surgical Resection and HIFU’s Role

All 5 patients had undergone both HIFU therapy for liver metastases and surgical resection of liver metastases. The interval between HIFU and surgery varied widely: 17 days, 67 days, 252 days, 456 days, and 1361 days. These intervals indicate that HIFU was used either as short-interval local consolidation prior to resection or as long-term local control before delayed resection, depending on clinical context.

3.3. Safety Profile

A total of six HIFU sessions were performed across five patients. All adverse events (AEs) were graded per CTCAE v5.0 and were Grade 1–2. Transient elevation of ALT/AST occurred in all patients and returned to baseline within 7 days. Three patients reported mild pain. All patients developed self-limiting subcutaneous/abdominal wall edema along the acoustic pathway, which was managed with conservative measures (e.g., cold compresses). No procedure-related skin burns or febrile reactions were observed, and no Grade ≥3 AEs occurred within 30 days (Table 2).

Table 2.

Types and Incidences of Adverse Events During HIFU Treatment (Within 7 days)

Adverse reactions after treatment	No.1	No.2	No.3	No.4	No.5
Any adverse event	Present	Present	Present	Present	Present
Fatigue	No	No	No	No	No
Pain	Present	No	Present	Present	Present
Fever	No	No	No	No	No
Soft tissue edema	Obvious edema	Obvious edema	Edema present	Mild edema	Mild edema
Skin burn	No	No	No	No	No
Elevated alanine aminotransferase	Present	Present	Present	Present	Present
Elevated aminotransferases	Present	Present	Present	Present	Present
No adverse events of grade 3 or above

3.4. Treatment Efficacy

We reviewed serial contrast-enhanced MRI and/or contrast-enhanced CT images from five patients at predefined time points: pre-HIFU, early post-HIFU, pre-hepatic surgery, early post-surgery, and last follow-up. Before HIFU treatment, the lesion was hypointense on T1-weighted imaging with peripheral rim enhancement and a targetoid (‘bull’s-eye’) appearance. On early post-HIFU imaging, the treated lesion demonstrated post-ablation changes with thin peripheral rim enhancement, which was interpreted as peri-ablational change/possible residual viable tumor. Before surgery, the lesion was slightly larger than that after HIFU treatment, and the enhanced range was expanded, suggesting tumor progression. After surgery, the lesion exhibited a short T1 signal, with a residual mild enhancement area at the edge of the lesion. Regarding the last follow-up, due to the different metastatic conditions of the tumor and its treatment process, the lesion in the surgical area showed little change; however, new lesions appeared in the liver. Representative imaging is shown in Figure 1.

Figure 1.

Imaging Images of Patient No. 1-5. (A1-E1) Before HIFU treatment; (A2-E2) After HIFU treatment; (A3-E3) Before recurrent surgery; (A4-E4) After recurrent surgery; (A5-E5) Last follow-up

Low-power view (left): Multiple irregular, angulated tumor nests with jagged borders infiltrating liver parenchyma, surrounded by prominent pink desmoplastic stroma. High-power view (right): Tumor cells exhibit moderate to marked nuclear pleomorphism, hyperchromatic nuclei with prominent nucleoli, high nuclear-to-cytoplasmic ratio, and frequent mitotic figures. Scattered single-file arrangements of neoplastic cells are noted within the dense fibrous stroma (Figure 2).

Figure 2.

Postoperative pathological image of liver metastasis

3.5. Survival Follow-Up

With a follow-up duration after HIFU ranging from 28 to 74 months, only one patient died at the last follow-up. The median progression-free survival (PFS) was 17.6 months. The 1-year and 2-year PFS rates were both 40%. OS ranged from 35 to 84 months, with a median survival of 63.8 months. The OS rates were: 1-year survival: 100%; 2-year survival: 100%; 3-year survival: 80%; 5-year survival: 60%. HIFU OS ranged from 28 to 74 months, with a median survival of 51.4 months. The 1-, 2-, 3-, and 5-year OS rates were 100% (5/5), 100% (5/5), 80% (4/5), and 60% (3/5), respectively. Kaplan-Meier curves are presented in Figure 3.

Figure 3.

The Kaplan-Meier survival curves show the Progression-Free Survival (PFS), Overall Survival (OS), and HIFU-related Overall Survival (HIFU-OS) of the 5 patients

3.6. Brief Summary of Individual Cases

To better illustrate the clinical course and the role of HIFU in each patient, a brief summary of the five cases is provided. For Patient 1, HIFU initially achieved a complete radiologic response, but intrahepatic recurrence developed 4 months later. The patient subsequently received additional systemic therapy followed by delayed hepatectomy, indicating that although HIFU provided effective initial local control, it was insufficient to prevent further disease progression in the setting of aggressive tumor behavior. For Patient 2, HIFU also achieved an initial complete response, with hepatic recurrence occurring 8 months later. A second HIFU session again yielded complete response, suggesting that repeated local ablation was feasible and well-tolerated; however, this case also underscores the necessity of close post-procedural surveillance and careful integration with subsequent multidisciplinary management. For Patient 3, complete response was attained after the first HIFU treatment, but intrahepatic recurrence developed at 14 months, followed by hepatectomy and additional multimodal therapy, reflecting a salvage role for surgery following transient local control by HIFU. For Patient 4, the lesion demonstrated only partial radiologic response after HIFU administered following systemic therapy, and hepatectomy was subsequently performed because residual viable tumor could not be ruled out. Postoperative histopathology confirmed residual adenocarcinoma, highlighting the inherent limitation of imaging-only evaluation after HIFU ablation. For Patient 5, the treated lesion remained radiologically controlled for an extended period after HIFU, and hepatectomy was ultimately performed due to newly developed hepatic metastatic lesions rather than progression of the originally ablated focus. Collectively, these cases indicate that the clinical role of HIFU in the management of CRLM is heterogeneous across patients, encompassing transient local control, repeated local consolidation, bridging to surgery, and facilitating delayed surgical intervention, depending on individual tumor dynamics and subsequent disease course.

4. Discussion

This case series describes the treatment trajectories of patients with colorectal liver metastases (CRLM) and explores the potential role and feasibility of incorporating High-Intensity Focused Ultrasound (HIFU) within multimodal conversion therapy. In this series, HIFU was not used as definitive monotherapy but rather as a potential adjunct local modality, functioning as either a bridging local therapy prior to surgery or a modality for local control over the observed follow-up period.

4.1. Clinical Advantages and Technical Differences of HIFU

The non-invasive nature of HIFU may confer distinct clinical benefits in managing CRLM. It may reduce puncture-related risks associated with percutaneous approaches (e.g., bleeding, infection, and tract seeding).^48,49 Its precision in energy delivery may help preserve functional liver parenchyma, which is critical for patients with limited hepatic reserve (e.g., impaired liver function) or contraindications to major resection. Additionally, the absence of ionizing radiation and the feasibility of repeated treatments may broaden its applicability in selected complex clinical scenarios.⁴² Notably, HIFU may be used to target lesions situated in challenging locations—such as those adjacent to major vasculature or the diaphragm³⁹—where the heat-sink effect or risk of collateral damage might constrain the use of other thermal ablation modalities (e.g., RFA/MWA).⁶³ Furthermore, HIFU serves as a thermal ablative technique that can achieve partial or complete tumor ablation. Its major advantages include its non-invasive nature and the feasibility of repeated treatment. In complex cases of colorectal liver metastases with high tumor burden, a study of ultrasound-guided focused ultrasound surgery (USgFUS) reported that HIFU allowed safe targeting of lesions without serious adverse events, while repeat HIFU remained feasible in the event of recurrence.⁵⁸

4.2. HIFU as a “Bridge to Surgery”: Limitations of Imaging-Based Response Assessment

The concept of employing HIFU as a non-invasive bridge aiming to achieve radiologic no evidence of disease (NED) after conversion therapy is conceptually appealing. Patient 4 represented a case in which this strategy was pursued, achieving a radiologic partial response (PR) after conversion chemotherapy and targeted therapy, followed by HIFU. However, the subsequent decision to proceed with hepatectomy (curative-intent resection) and the pathological findings—which demonstrated residual viable adenocarcinoma in multiple foci (moderately differentiated)—were discordant with the imaging-based PR assessment. This discrepancy suggests that conventional CT/MRI may be limited for assessing residual viability after HIFU in CRLM, particularly when differentiating complete ablation (technical efficacy) from residual viable tumor. Ablation coverage may be affected by respiratory motion and heat-sink effects near adjacent vessels, potentially resulting in residual viable tumor. Therefore, imaging findings alone may be insufficient to support replacing curative-intent resection with HIFU, and should be interpreted with caution.

4.3. Delineating the Role of HIFU: Salvage Surgery Versus Planned Surgery

The clinical implications of hepatectomy following HIFU varied in timing and indication between patients, highlighting the importance of contextualizing its role. Patient 3 required salvage surgery within 3 months post-HIFU due to contrast-enhanced imaging findings suggestive of residual viable tumor, suggesting limited local control in this case. In contrast, Patient 5 maintained radiologic stability of the treated lesion for 45 months after HIFU, ultimately undergoing hepatectomy for newly detected hepatic metastases on PET/CT. In this instance, HIFU delayed invasive resection for years, potentially reducing the need for early surgery; quality-of-life outcomes were not formally assessed. This contrast highlights the importance of clearly defining the intended role of HIFU (definitive/curative-intent vs bridging/local control) in both clinical decision-making and future studies.

4.4. Synergy Between HIFU and Systemic Therapy

All five patients received systemic therapy, and clinical outcomes appeared to depend on the effectiveness of concurrent or subsequent systemic treatment. The favorable course in Patient 5 coincided with sustained disease control on cetuximab-based therapy. Here, HIFU may have contributed to local control by ablating residual lesions after systemic therapy; however, tumor clonality and mechanisms of drug resistance could not be assessed in this study. This observation is consistent with the rationale for integrating local and systemic approaches in metastatic disease. Conversely, in patients with aggressive disease biology or extensive metastatic burden (e.g., recurrent hepatic relapse in Patient 1), HIFU provided local tumor control but did not prevent subsequent disease recurrence/progression. Thus, in this small case series, durable benefit from HIFU appeared more likely when combined with effective systemic therapy, and HIFU should be considered as part of a comprehensive multimodal strategy rather than employed in isolation.

4.5. Study Limitations

This study has several limitations inherent to its retrospective design, small sample size, and single-center origin, which may introduce selection bias and constrain the generalizability of the findings. The absence of a control group precludes isolating the contribution of HIFU to clinical outcomes (e.g., local control or resectability), as outcomes likely reflected the combined effects of multimodal therapy. Several additional limitations should be noted. First, the interval between HIFU and subsequent hepatectomy varied markedly across patients, reflecting individualized rather than standardized treatment sequencing. This limits case comparability and makes it difficult to define clear selection criteria. Second, because all patients received multimodal treatment and no control group was included, the observed outcomes cannot be attributed to HIFU alone. Third, although HIFU appeared to delay surgery in some patients, quality-of-life outcomes were not formally assessed. Finally, while HIFU may have synergistic effects with systemic therapy, no mechanistic evaluation was performed in this series, and this possibility remains speculative. In terms of imaging assessment, conventional contrast-enhanced MRI alone may be insufficient to detect minimal residual viable tumor after HIFU. Future studies should further evaluate more sensitive assessment methods, such as functional imaging or ctDNA-based monitoring, particularly when imaging is used to guide decisions on delaying surgery.

4.6. Future Perspectives

Building on our findings, future efforts should focus on: 1) Refined Patient Selection: Leveraging tools like radiomics and artificial intelligence to pre-treatment predict technical efficacy (complete ablation) and local control after HIFU. Hypothesized candidates for further study include those with oligometastases (e.g., ≤3 lesions), tumors <3 cm, lesions away from major vessels, and patients demonstrating good response to prior systemic therapy (e.g., Patient 5); these criteria require prospective validation. 2) Technical Optimization: Developing real-time thermometry (e.g., MR thermometry where available) and closed-loop feedback systems to enhance ablation precision and completeness, thereby mitigating perfusion-mediated heat loss. 3) Innovative Response Assessment: Exploring the utility of functional imaging (e.g., DWI, DCE-MRI) and liquid biopsy approaches (e.g., ctDNA) to explore minimal residual disease (MRD) monitoring post-HIFU, to complement conventional anatomical imaging.

5. Conclusion

In summary, this case series suggests that HIFU may be safely and feasibly integrated as a local consolidative therapy within multimodal treatment sequences for selected patients with CRLM deemed unresectable at baseline by multidisciplinary assessment, and was followed by R0 resection in these cases. A notable observation is the marked heterogeneity in the HIFU-to-surgery interval, which likely reflects individualized sequencing based on systemic therapy response, tumor biology, and surgical candidacy, suggesting that HIFU may serve different functions beyond focal ablation within individualized treatment sequencing. Our data suggest at least two potential roles in this small series: as an immediate consolidative therapy for rapid resection and as a means of prolonged local control prior to delayed resection, the latter potentially valuable for maintaining function and controlling limited-volume progression; however, quality-of-life outcomes were not formally assessed in this study. Preclinical and early clinical evidence indicates that HIFU may have immunomodulatory effects^57,64-67 and could potentially synergize with systemic treatments to extend the duration of local control or delay hepatic progression, a hypothesis that warrants further investigation. Prospective studies, ideally with controlled comparative designs, are needed to validate these findings, compare HIFU-containing sequences against standard local therapies (e.g., RFA/MWA/SBRT) plus systemic treatment, and identify candidate predictive biomarkers for optimal patient selection.

Footnotes

Acknowledgments

The authors would like to express their gratitude to all contributors who provided technical support, data collection, or valuable discussions during the preparation of this manuscript but do not meet the criteria for authorship.

ORCID iD

Guangtan Du

Ethical Considerations

This study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (Approval No. QYFY WZLL 30817). All procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

Consent to Participate

Written informed consent was obtained from all participants.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the Qingdao Medical and Health Excellent Youth Talent Training Project, and the Qingdao University Clinical+X-plan Project (QDFY+X2023104).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.*

Appendix

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