Analysis of the results of high-intensity focused ultrasound for patients with advanced pancreatic cancer

Abstract Objective To investigate the safety, local ablation efficacy, analgesic effects, and factors influencing the survival of patients with advanced pancreatic cancer treated with high-intensity focused ultrasound (HIFU). Materials and methods Patients with advanced pancreatic cancer who underwent HIFU for the first time at the Suining Central Hospital between January 2018 and September 2022 were enrolled. The efficacy of tumor ablation was assessed using enhanced computed tomography (CT) and magnetic resonance imaging (MRI), pain relief was assessed using the visual analog scale (VAS), and complications and survival rates were investigated. The Kaplan–Meier method and a Cox regression model were used to analyze the independent risk factors that may have affected prognosis. Results Intraoperative ultrasonography showed varying degrees of grayscale changes in all cases. One month after surgery, enhanced computed tomography or magnetic resonance imaging examinations showed complete or partial responses in 85.22% of the patients. Pain relief was achieved in 98.21% of the patients. No postoperative complications of SIR-C grade or higher were observed. The overall median survival time (MST) was 12.1 months. Cox multifactorial analysis showed that the main factors affecting overall survival (OS) were clinical stage, preoperative liver function, and combination chemotherapy. Conclusion HIFU is safe and effective for pancreatic cancer treatment, and has the potential to become an important supplement for the treatment of advanced pancreatic cancer. This approach needs to be further verified by multi-center and large-sample studies.


Introduction
Pancreatic cancer is a malignant tumor of the digestive system, with rising global incidence and extremely high morbidity and mortality rates [1,2].Surgery is the treatment of choice for patients with pancreatic cancer.However, only 20% of patients are indicated for surgery upon diagnosis.Despite advancements in surgical concepts and improvements in surgical techniques for pancreatic surgery, the 5year survival rate associated with pancreatic cancer remains less than 10% [3].For patients who are not eligible for surgery, it remains a challenge to find treatment modalities that improve patients' quality of life and prolong survival.
High-intensity focused ultrasound (HIFU) is a technique that has gradually developed and matured in recent years, and has been increasingly used in the treatment of pancreatic cancer over the last decade because of its advantages such as its relatively noninvasive nature, rapid postoperative recovery, and less pain for patients.Several recent studies have shown that HIFU can be used to effectively treat patients with pancreatic cancer [4,5].However, these studies showed different survival times and symptom-relief rates [6,7].Therefore, the aims of this retrospective study were to investigate the safety, local ablation efficacy, and analgesic effects of HIFU, along with factors influencing the survival of patients with advanced pancreatic cancer treated using this approach.

Materials and methods
This retrospective study was approved by the ethics committee of our institute (no: KYLLMC20230010), and all patients signed an informed consent form before undergoing HIFU treatment.

Patients
A total of 88 patients with advanced pancreatic cancer treated with HIFU for the first time at Suining Central Hospital from January 2018 to September 2022 were enrolled in this study.The inclusion criteria were as follows: (1) patients who met the diagnostic criteria for pancreatic cancer, confirmed by pathological puncture biopsy, or were clinically diagnosed with pancreatic cancer by imaging assessments (computed tomography [CT], magnetic resonance imaging [MRI], or positron emission tomography [PET]-CT), and (2) patients with unresectable stage III or IV pancreatic cancer according to the 8th edition of the American Joint Committee on Cancer.The exclusion criteria were as follows: (1) estimated life expectancy of less than 3 months, (2) non-eligibility for general anesthesia, (3) tumors not visible on ultrasound, (4) combined obstructive jaundice and poor effect after biliary drainage treatment: total or direct bilirubin levels remained greater than 1.5 times the upper limit of normal values, (5) recurrence after Whipple surgery, (6) massive ascites, and (7) extensive scarring along the acoustic pathway.

Preparation before HIFU treatment
Since pancreatic cancer lesions are adjacent to the stomach and duodenum, specific bowel preparation is mandatory.The patients were asked to ingest semiliquid meals for 2 days, after which they ingested only liquid food, while avoiding gas-producing food, and then fasted for 12 h.Enema was performed before HIFU on the treatment day.On the day of the treatment, a gastric tube was placed and cold normal saline was used to construct a safe acoustic pathway to protect the stomach and duodenum from thermal damage.Skin preparation included shaving the hair on the upper abdominal wall and degreasing and degassing with 70% ethanol and degassed water.

HIFU ablation
HIFU ablation for pancreatic cancer was performed under general anesthesia using a Focused Ultrasound Tumor Therapeutic System (Model-JC; Chongqing Haifu Medical Technology Co., Ltd., Chongqing, China) equipped with an ultrasound imaging probe (MyLab 90; Esaote, Genova, Italy) for real-time monitoring during treatment.Therapeutic ultrasound was generated by a transducer with a frequency of 0.8-1.0MHz, focal length of 15 cm, and diameter of 20 cm.The patients were carefully positioned prone on the HIFU treatment table with the anterior abdominal wall in contact with degassed water.A degassed water balloon was placed between the abdominal wall and transducer, which was used to push the bowel away from the acoustic pathway by adjusting its size and tension to prevent bowel injury.
The sagittal ultrasound scanning mode was selected.A treatment plan was created by dividing the lesion into different slices with a distance of 5 mm between slices.Point scanning was performed with sonication power between 300 and 400 watts.When the input power was 400 watts, the calculated focal acoustic intensity exceeded 10000 W/cm 2 .Treatment began from the innermost slice, and the focus was maintained at least 1 cm from the boundary of the tumor.During the procedure, the HIFU therapeutic power was adjusted on the basis of changes in the grayscale of the treated area on ultrasonographic imaging.HIFU treatment was terminated when an increased grayscale covered the treated tumor.Contrast-enhanced ultrasonography was then performed to evaluate the ablation volumes of the lesions.Heart rate, blood pressure, respiration, and oxygen saturation were monitored throughout the treatment.

Evaluation and follow-up
1. Efficacy of local treatment: Because some patients with pancreatic cancer in the head of the pancreas had a metallic stent and were contraindicated for MRI, we used different imaging modalities (CT and MRI).Evaluation criteria refer to previous similar studies [8,9].Tumor response was evaluated using enhanced CT or MRI 1 month after HIFU treatment.Complete response (CR) was defined as total resolution of all evidence of the primary tumor.A partial response (PR) required a 50% reduction in the maximum perpendicular tumor measurements for at least 1 month.Stable disease (SD) was defined as a <50% reduction or <25% increase of measurable tumor lesions.Patients were considered to have progressive disease (PD) if the measurable tumor lesions increased by greater than 25% according to initial staging.2. Complications: The incidence and severity of each type of complication were evaluated using the SIR classification criteria for complications recommended by the Society of Interventional Radiology Clinical Practice Guidelines [10].Adverse effects and complications were observed from the beginning of treatment to 1 month after HIFU. 3. Pain relief: All patients were assessed using the visual analog scale (VAS), with a score of 0 representing no pain and 10 representing the most severe pain.For patients who did not take opioids before HIFU but took conventional analgesics, the pain score before requiring oral analgesics was recorded.For patients who required routine oral opioid analgesia preoperatively, the postoperative analgesic doses were compared to the preoperative doses.Follow-up examinations were performed by outpatient evaluation or telephone assessments (once a month), from the time of discharge to the patient's death or the follow-up cutoff date of March 1, 2023. 4. Survival time: Considering the differences in disease stages when patients seek medical treatment, the date of the patient's first HIFU treatment at our hospital is set as the starting point, and death from pancreatic cancer is the endpoint event.

Statistical methods
SPSS26.0 software (IBM SPSS Inc., Chicago, IL, USA) was used for statistical analysis.Normally distributed data were expressed as mean ± standard deviation (mean ± SD).Nonnormally distributed data were presented as median and interquartile range.The v 2 test was used to compare count data.The Kaplan-Meier method was used to calculate survival; the log-rank method was used to compare differences between groups; and the variables affecting survival were analyzed using a Cox regression model with multiple factors.p < 0.05 was considered statistically significant.

Baseline characteristics
As shown in

Pain relief after HIFU
We used VAS scores to assess analgesia in patients who did not take oral opioids at regular intervals and observed the postoperative drug doses in patients who took oral opioids at regular intervals.A total of 66 patients did not take opioid drugs regularly, of which 21 had severe pain, 37 had moderate pain, and eight had mild pain.The mean VAS pain score was 6.66 ± 2.3 (range: 2-9) before HIFU treatment.
After HIFU treatment, 65 patients reported pain relief, with an overall relief rate of 98.48% (65/66), and the VAS score decreased to 2.97 ± 1.9 at 3 days after HIFU (p < 0.005).Among these 65 patients, 14 patients, including three patients with severe pain, six patients with moderate pain, and five patients with mild pain, reported that their pain disappeared; 35 patients, including 28 patients with moderate pain and seven patients with severe pain, reported that their pain reduced to mild pain; and 11 patients with severe pain reported that their pain reduced to moderate pain.Three patients with moderate pain and two patients with mild pain reported reduced pain scores but no significant relief.Only one patient with mild pain did not experience pain relief.The follow-up results showed that the average pain scores in the six consecutive months were as follows: 3.15 ± 1.8, 3.35 ± 1.8, 4.06 ± 2.0, 5.03 ± 1.9, 5.96 ± 2.1, and 6.52 ± 2.2 (Figure 2).Three of these patients underwent HIFU treatment again 6 months later, due to recurrence, to alleviate pain.
Among the 22 patients who had been taking oral opioids regularly before HIFU, all reported a reduction in analgesic use after HIFU: three patients no longer required oral analgesia, 14 patients reported a 2/3 reduction in dosage, and five patients reported a 1/2 reduction.

Safety evaluation of HIFU
During and after treatment, the vital signs of all patients remained stable.Fifteen patients reported pain in the treated area after HIFU, with an average pain score of 5.07 ± 1.91.Among them, seven patients received intravenous pethidine hydrochloride, and postoperative pain was relieved within 12 h.Two patients had fever with temperature below 38.5 C. One patient developed skin burns (superficial grade II, large, thin blisters without specific treatment).All of these were classified as SIR-A and SIR-B adverse effects.No complications of SIR-C grade or higher were observed (Table 2).

Survival after HIFU
By the end of March 2023, three of the 88 patients were lost to late follow-up, and the follow-up rate was 96.59%.Overall,  disease.The 6-month survival rates were 92.7% and 86.4% in patients with stage III and IV disease, respectively.The 1-year survival rate was 68.3% in patients with stage III disease and 34.1% in patients with stage IV disease.The 2-year survival rates were 14.6% and 9.1% in patients with stage III and IV disease, respectively.

Univariate analysis
Univariate analysis showed that tumor stage, pre-HIFU liver function abnormalities, ablation efficacy, and chemotherapy were factors influencing overall survival (OS) (Table 3 and Figure 3).The factors that were statistically significant in the univariate analysis were included in the multi-factor analysis, and the results of the Cox proportional risk regression model showed that tumor stage, pre-HIFU liver function abnormalities, and chemotherapy were significant influencing factors (Table 4).

Discussion
Traditional systemic chemotherapy and radiotherapy are often used in patients with advanced PC. Local treatments, including stereotactic radiotherapy (SBRT), radiofrequency ablation (RFA), irreversible electroporation (IRE), HIFU, and regional intra-arterial chemotherapy are also used in the management of patients with advanced pancreatic cancer [11][12][13].Combination chemotherapy regimens are the standard of care for advanced disease; however, these regimens are associated with substantial toxicity [14].A meta-analysis showed that the survival rates in patients with advanced pancreatic cancer have minimally improved using different chemotherapy regimens [15].Local treatments can achieve some therapeutic effects, including SBRT, radiofrequency ablation (RFA), and IRE; however, these methods also have drawbacks.SBRT can lead to radiation-related complications [16].RFA is a common method of thermal ablation that is contraindicated for small tumors with a perivascular growth pattern, because a safety margin of at least 5 mm from the ablation zone is necessary, to avoid thermal damage to vital structures [17].IRE can be used to treat tumors adjacent to vascular structures but it is a relatively complex and expensive technique, with high risk, requiring careful evaluation of patients before the procedure [11].HIFU is a noninvasive thermal ablation treatment that causes cell destruction and tissue necrosis mainly through thermal and mechanical effects [18].A previous study showed that the energy used in HIFU does not have a significant effect on blood vessels larger than 200 lm in diameter, which is an important basis for the implementation of this treatment in patients with advanced pancreatic cancer with encapsulated tumors adjacent to large vessels [19].In this study, HIFU was performed safely.The most common adverse effect was pain in the treated area, and none of the patients required specific treatment for the pain or showed serious complications.Post-HIFU CT or MRI revealed a non-perfused volume (defined as ablated volume) in every lesion of pancreatic cancer, and the patients reported significant pain relief after HIFU treatment.Cancer pain is an important factor that affects the quality of life of patients with advanced pancreatic cancer.A pancreatic cancer network health survey reported that 93% of patients experienced pain, of which 83% experienced moderate or severe pain [20].Effective pain relief is the main objective of treatment for advanced pancreatic cancer.Previous studies have reported significant pain relief in patients with pancreatic cancer after HIFU treatment [21,22].The pain relief may be caused by the heat generated by HIFU in the focal area, which induces tumor necrosis, thus eliminating pressure on the nerves and relieving pain.In addition, HIFU treatment partially or completely blocks the pain transmission pathway by directly destroying the tumorinvaded abdominal plexus to achieve pain relief [23,24].Cavitation or acoustic pressure can temporarily modify cell morphology, causing dysfunction of membrane proteins and stretch-activated ion channels, resulting in an imbalance in cation influx and subsequent alteration of membrane potential.These changes alter neuronal excitability and propagation of action potentials, with pain palliation achieved by neuromodulation of noxious stimuli in the central or peripheral nervous system [25].The patients in this study showed significant pain relief after HIFU therapy, with an overall relief  rate of 98.53%, and the pain-relieving effect peaked within 3 days postoperatively and lasted for 3 months before gradually decreasing thereafter.This is consistent with the findings of other studies in which pain was usually relieved 1-2 days after HIFU treatment and the analgesic effect lasted for an average of 10 weeks [8].However, the pain gradually returned to pretreatment levels 5-6 months after treatment.
The short-term nature of this pain relief may be explained by the fact that HIFU is currently a local, palliative treatment for pancreatic cancer, and the cases in this study all involved advanced tumors; as the tumor developed further and grew, it compressed the nerves again.Therefore, HIFU treatment for pancreatic cancer should deliver more energy to achieve better long-term results with a large no-perfusion volume (NPV).In addition, three patients in this study underwent HIFU treatment again, 6 months after the first, suggesting that this treatment can be repeated for patients with advanced pancreatic cancer without severe adverse effects.
Several recent studies have shown that HIFU combined with other treatment modalities can have synergistic sensitizing effects.The long-term prognosis of HIFU combined with systemic chemotherapy has been reported to be significantly better than that of chemotherapy alone [26,27].In this study, the Cox multi-factor analysis of single factors affecting OS also revealed that combined chemotherapy was a more important influencing factor than local ablation efficacy.HIFU combined with chemotherapy (especially gemcitabine) has even been suggested to potentially become a new therapy for pancreatic cancer [28].The synergistic effects of HIFU are generally believed to increase vascular permeability through intravascular cavitation and thermal effects, making it easier for chemotherapeutic drugs to cross the blood vessels and enter the tumor stroma [29].The present study showed that the efficacy of local ablation was not a significant factor affecting OS, suggesting that HIFU therapy alone may not be effective in prolonging the prognosis of advanced pancreatic cancer and that multiple treatments, such as combination chemotherapy, may be required to prolong the survival of such patients.
This study had some limitations.First, this was a retrospective study with a small sample size from a single center, which may have led to bias in the results of the survival analysis.In addition, the energy delivered to the pancreatic cancer was not standardized.Therefore, a multicenter prospective study should be conducted to validate our findings.

Conclusions
HIFU is safe and effective in the treatment of advanced pancreatic cancer.This approach can be used for pain control and inhibition of tumor progression in advanced pancreatic cancer and may become an important supplement to the treatment of this type of cancer.However, future multi-center studies with large sample sizes are needed to validate the findings of this study.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Figure 1 .
Figure 1.Efficacy of HIFU ablation.(1) Pretreatment ultrasound images.(2) Post-treatment ultrasound image showing overall grey scale changes in the target area.(1) and (2) are taken from the same patient.(3) Pretreatment CT presentation of pancreatic body caudal tumor.(4) Follow-up enhanced MRI after 1 month of treatment, with no enhancement in the area of the lesion (indicated by the arrow) and significant coagulative necrosis of the lesion seen in delayed phase.(3) and (4) are taken from the same patient.

Figure 3 .
Figure 3. Results of single-factor analysis affecting OS.(a) Effect of local response rate on OS: Patients with complete response (CR) and partial response (PR) had a significantly better prognosis than those with stable disease (SD) and progressive disease (PD).(b) Effect of combination chemotherapy on OS.(c) Effect of tumor staging on OS.

Table 1 .
Patient characteristics and therapeutic parameters.
61 (69.32%) patients died, and 24 (27.27%) were still alive and under follow-up.The overall median survival time (MST) was 12.1 months (interquartile range: 2.3-47 months).The MST was 13.7 months (interquartile range: 3.2-47 months) for patients with pancreatic cancer stage III versus 9.1 months (interquartile range: 2.3-40.3months) for patients with stage IV disease.The 3-month survival rate was 100% in patients with stage III disease and 97.7% in those with stage IV

Table 2 .
SIR classification of complications of patients treated with HIFU.

Table 3 .
Log-rank one-way analysis of factors affecting OS.

Table 4 .
Multi-factor analysis of Cox affecting OS.