Abstract
Pancreatic cancer (PC) has one of the poorest prognoses among solid cancers, and its incidence has increased recently. Satisfactory outcomes are not achieved with current therapies; thus, novel treatments are urgently needed. High-intensity focused ultrasound (HIFU) is a novel therapy for ablating tissue from the outside of the body by focusing ultrasonic waves from multiple sources on the tumor. In this therapy, only the focal area is heated to 80–100 ºC, which causes coagulative necrosis of the tissue, with hardly any impact on the tissue outside the focal area. Although HIFU is a minimally invasive treatment and is expected to be useful, it is not yet generally known. Here, we discuss the usefulness of HIFU treatment for un-resectable advanced PC using the results of previous research, meta-analyses, and systematic reviews on its efficacy and safety. HIFU therapy for un-resectable PC is useful for its anti-tumor effect and pain relief, and is expected to prolong survival time and improve quality of life. Although HIFU for PC has several limitations and further study is needed, this technique can be safely performed on un-resectable advanced PC. In future, HIFU could be utilized as a minimally invasive treatment strategy for PC patients with a poor prognosis.
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.Avoid common mistakes on your manuscript.
Introduction
Pancreatic cancer (PC) has an increasing incidence and a 5-year overall survival rate of approximately 7%, one of the poorest prognoses among solid cancers [1]. Despite the numerous methods for early diagnosis, 60–70% of all PCs are un-resectable. Furthermore, the severe pain caused by advanced PC is extremely difficult to treat and may greatly affect the patient's quality of life (QOL). Moreover, chemotherapy and chemo-radiotherapy are the standard of care for un-resectable PC, but their outcomes are not satisfactory, with a median survival time (MST) of only 7 months. Thus, novel treatments for PC with a poor prognosis are needed. In recent years, high-intensity focused ultrasound (HIFU)—a minimally invasive treatment that does not involve radiation exposure, needles, or anesthesia—has garnered attention [2,3,4]. Moreover, the results of clinical trials with a large number of patients and their long-term outcomes have been published, and expectations for the clinical application of HIFU have accelerated. In this review, we discuss the principles of HIFU as well as the equipment, mechanisms of its effects, and indications of HIFU. Further, we examine HIFU for PC in general and contrast the outcomes of HIFU in Japan and worldwide. Lastly, we summarize systematic reviews and meta-analyses on HIFU for PC and highlight new developments in the field.
About HIFU
Principles of HIFU
While ultrasound (US) is often used in diagnostic equipment, it also has therapeutic applications in hyperthermia, HIFU, and histotripsy. Hyperthermia is the use of the thermal action of ultrasonic waves, whereas HIFU heats tissue to a greater degree and in a more focused manner to cause coagulative necrosis. Because of differences in their irradiation conditions, HIFU mainly leverages thermal and mechanical actions, whereas histotripsy uses mechanical action via cavitation. Specifically, HIFU cauterizes tissue from outside the body by focusing ultrasonic waves from a transducer with many ultrasonic sources on a single point, known as the target tumor [2,3,4]. This modality is groundbreaking because it only causes coagulative necrosis via thermal and non-thermal energy (mainly cavitation) to the focal area, with hardly any impact on the intervening tissue outside the focal area. Moreover, the ultrasonic waves are emitted from multiple sources inside a semicircular probe, and the vibrational energy converges on the center of the curvature or the focal region [2,3,4] (Fig. 1). Depending on the absorption coefficient of the tissue, the vibrational energy is converted to heat at 80.0–98.6 ºC. The temperature of the tissue in the focal region increases quickly (generally within 1 s), but there is hardly any effect on healthy tissue outside the focal area because the temperature decreases to 50 ºC 7–8 mm away. Therefore, this technique does not require general anesthesia, epidural anesthesia, sedation, or analgesics.
Principles of HIFU. HIFU is performed by ablating tissue from outside the body by focusing ultrasonic waves on a single target tumor. The ultrasonic waves are emitted from multiple sources placed inside a semicircular probe, and this vibrational energy converges on the center of the curvature, also known as the focal region. HIFU, high-intensity focused ultrasound
Equipment
HIFU requires different equipment depending on whether it is used for external or trans-rectal irradiation, which is mainly used for treating the prostate. External irradiation devices are guided by magnetic resonance imaging (MRI) or US. MRI-guided devices are mainly used to treat the uterus and mammary glands. MRI-guided therapy is beneficial in that it is not affected by patient factors such as obesity. Additionally, this modality can be used to perform objective assessments, and it is available at many facilities. However, MRI-guided therapy has a high equipment cost, is laborious and time-consuming, and the time available for treatment may be limited because the equipment is prioritized for regular examinations. Additionally, the treatment site cannot be observed in real time, the spatial resolution is low compared with US, and the treatment site must be large to use MRI. In contrast, with US-guided therapy, the lesion can be monitored in real time, the spatial resolution is high, the treatment and displayed images are both US images facilitating the process, evaluating therapy is easy with contrast-enhanced US, and the cost is low. Additionally, US-guided therapy can be used on abdominal organs that have peristaltic movement, and treatments can be performed safely and accurately by observing the treatment site in real time.
Biological effects of ultrasonic waves and the mechanism of HIFU’s effects
US is a diagnostic tool widely used worldwide with the potential to shift from the diagnostic to the therapeutic realm by changing the intensity and irradiation time of the ultrasonic waves [5, 6]. The energy level of HIFU is about 103 times that of ultrasonic devices used for imaging, which is much lower than that of proton beams or X-ray computed tomography. Ultrasonic waves have two biological actions: thermal (heating) and non-thermal (mainly cavitation) [5, 6]. Heating occurs when the ultrasonic waves propagate and are scattered or absorbed, by which the ultrasonic energy converts into thermal energy. If the target lesion causes severe scattering, it will generate intense heat at the site. Moreover, the biological action of ultrasonic waves is a linear correlation of irradiation intensity × time. That is, when a threshold value is exceeded, the biological actions occur, and a therapeutic effect is elicited (Fig. 2). The recommended focal temperature for HIFU is ≥ 55 ºC with 15 s of irradiation. In practice, coagulative necrosis can be achieved by irradiation for only a few seconds at a focal temperature of ≥ 60 ºC.
Schematic diagram of the zones for ultrasound diagnosis and treatment. The biological action of ultrasonic waves is a linear correlation of irradiation intensity × time. That is, when a threshold value is exceeded, the biological action occurs, and a therapeutic effect is elicited. By increasing the intensity of the ultrasonic waves and their irradiation time, the threshold between the safety zone of ultrasound diagnosis is exceeded, and the ultrasound treatment zone is entered. Thus, HIFU is in the ultrasound treatment zone
The radiation pressure and vibration of ultrasonic waves also cause non-thermal effects, mainly due to cavitation. Cavitation is a phenomenon in which a vacuum is created when a high-amplitude ultrasonic vibration is applied to a liquid. The vacuum gradually grows and then collapses, causing tissue and cell damage by destroying cell membranes or rupturing capillaries. The therapeutic effects of HIFU are caused by heating and cavitation, which cause coagulative necrosis, degeneration, apoptosis, cell destruction, and fibrosis [2,3,4, 7,8,9,10,11,12,13,14,15].
Indications of HIFU
Patients should undergo HIFU (1) to achieve tumor ablation and pain relief from malignant tumors, such as PC, liver cancer, renal cancer, prostate cancer, bladder cancer, breast cancer, and soft tissue sarcoma; (2) to treat benign diseases, such as uterine myoma and prostatic hypertrophy; and (3) to treat neurological diseases, thrombolysis, arterial occlusion, bleeding, and hemostasis for vascular or organ hemorrhage.
HIFU for pancreatic cancer
Indications of HIFU for pancreatic cancer
HIFU is suitable for patients with PC with un-resectable advanced cancer that is not indicated for or does not respond to conventional local therapies or whose pain can only be controlled by increasing the dose of analgesics. Moreover, HIFU therapy is expected to improve the QOL of patients by preventing local complications such as duodenal obstruction through local control and symptom relief effects such as pain relief. In addition, it has been reported that local treatment activates the antitumor immuno-stimulatory effect (abscopal effect) and has antitumor effects on distant metastases and prolonged survival [11,12,13,14,15,16]. Therefore, the local treatment of advanced PC with distant metastasis is also an indication for HIFU therapy. However, there is a limit to where the focused ultrasonic HIFU waves can reach. The tumor depth cannot be more than approximately 10 cm from the skin surface; thus, deeper tumors are not indicated for this treatment. Therefore, cancers in the pancreatic tail are often not indicated for HIFU because of their depth, and the effects of gastrointestinal gas make these tumors difficult to visualize.
Complications
Complications of HIFU include skin burns, gastrointestinal perforation, digestive ulcers, gastrointestinal obstruction, acute pancreatitis, pancreatic pseudocysts, pancreatic leaks, obstructive jaundice, vascular obstruction, peritonitis, local infections, bleeding, hematoma formation in the lesion, and pain. Moreover, the pancreas is an extremely sensitive organ, and the effects of the heat from HIFU can cause severe inflammatory changes. No serious adverse events were reported in animal studies [2,3,4, 7,8,9,10,11,12,13,14,15]. In addition, no serious complications have been reported in clinical practice to date, and thus this modality is considered minimally invasive or noninvasive [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] (Table 1).
HIFU in practice
Contrast-enhanced ultrasonography (CEUS) should be performed by the day before treatment to formulate a treatment strategy with an appropriate treatment route, range, and relationship with surrounding organs. To prevent attenuation of the ultrasonic waves and enable visualization of the target tumor, patients should fast for 12 h and abstain from drinking for 4 h before treatment. Prior to HIFU, the patient is placed in the supine position to identify the appropriate treatment route and relationships with surrounding organs, and US is performed in B mode. Low-viscosity US gel for HIFU is applied to the treatment site. Unclear images due to gas in the intestine can be overcome by administering degassed water, dimethicone, or butylscopolamine to the patient, or increasing the pressure of the water bag, while sedatives are not usually necessary.
There are several US-guided HIFU devices. For example, the FEP-BY02 system made by Yunde Bio-Medical Engineering Co. (Beijing, China) is a specialized device with upper and lower transducers capable of depicting the tumor in detail during therapy and assessing the therapeutic effect afterward. The transducers in this system have 251 US emitters of 1.1 MHz on a 37-cm sphere that focus on a single fixed focus. The upper transducer is used to treat PC as it can be pressed against a patient in the supine position to depict the tumor. The water sac is filled with degassed water, the transducer is lowered to the treatment site, and the target is observed with an image confirmation probe while pressed lightly with the water sac. The confirmation probe and the therapeutic oscillator are on the same axis. Moreover, the treatment plan is formulated while observing the target; however, the visualization ability of the confirmation probe declines as it is lifted up during treatment. The thickness of the abdominal wall (skin, subcutaneous fat, muscles), distance from the skin to the target, and the size and depth of the tumor are measured to calculate attenuation from the tissue and surrounding environment, which is used to calculate the therapeutic dose. The treatment plan is entered into a computer, which controls the output power, treatment position, and other aspects during HIFU. If the distance to the surrounding major organs (stomach, spleen, liver, duodenum, and bile duct) is ≥ 1 cm, and blood flow in the superior mesenteric artery is weak or the vessel is thin, the distance from this vessel should also be ≥ 1 cm. Moreover, if the target is deep, the US waves will attenuate greatly during transmission (energy attenuates by about 20% for every 1 cm of depth); thus, the energy will be low when the target is reached, which could result in ineffective treatment. Because the area ablated by a single irradiation is small (3 × 3 × 10 mm), the entire tumor is ablated in layers. In practice, if cavitation occurs, the cauterization extends widely around the site.
During HIFU, patients are checked for pain in the abdomen, back, pelvic area, or skin. If the patient complains of abdominal pain that is more severe than before treatment or if skin pain occurs, treatment can be suspended until the pain is relieved. The initial power can be used after resuming treatment, or it can be reduced by 10% after treatment or if pain is experienced.
Outcomes of HIFU for pancreatic cancer
Outcomes of HIFU for pancreatic cancer (outside of Japan)
Table 1 shows the treatment outcomes and complications of HIFU performed outside of Japan. Pain relief was reported in 57–100% of patients with a mean of 81.8%. Further, survival was shown to be prolonged in the HIFU group in a number of studies [20,21,22, 28,29,30, 32, 37, 45, 51, 52, 54, 57, 58, 60,61,62, 68]. Specifically, Xie et al. [17] reported a clinical efficacy rate of 66.7% with HIFU alone and 76.6% with HIFU plus chemotherapy, and a response rate of 33.3% with HIFU plus chemotherapy and 14.3% with chemotherapy alone. Meanwhile, Wang et al. [29] reported a response rate of 50.0% with HIFU plus chemotherapy and 31.3% with chemotherapy alone. Moreover, Vidal-Jove et al. [45] reported a clinical response rate of 82% for HIFU in combination with chemotherapy in 48 cases of un-resectable PC and a MST of 13 months. The main complications observed in the study were pancreatitis with gastrointestinal hemorrhage and skin burns. Furthermore, Li et al. [52] compared HIFU in combination with S-1 chemotherapy to S-1 chemotherapy alone in 120 cases of metastatic PC after gemcitabine (GEM) failure. The MST was 10.3 months in the combination group, which was significantly longer than the 6.6 months in the chemotherapy alone group. The pain relief results were also significantly improved in the combination group as compared with the chemotherapy alone group (57% vs. 20%, P = 0.000). No serious complications were observed in this study. Ji et al. [57] reported a median overall survival of 12.2 months (95% confidence interval [CI] 11.1–12.7) for patients with HIFU therapy alone, combination with chemotherapy, and radiotherapy. The 6- and 12-month survival rates were 94.25% (95% CI 86.74–97.57%) and 50.85% (95% CI 38.17–62.21%), respectively. Complications included fatigue, abdominal pain, fever, nausea, and rash. Additionally, Marinova et al. [58] examined HIFU in 50 cases of un-resectable advanced PC and reported a median overall survival and progression-free survival of 16.2 and 16.9 months from diagnosis and 8.3 and 6.8 months from the intervention, respectively. In a study by Ning et al. [60] in 347 patients who underwent HIFU + GEM chemotherapy and 176 patients who received only GEM chemotherapy, the median overall survival was 7.4 and 6.0 months (P = 0.002), respectively. The survival rates of the two groups at 6 months, 10 months, 1 year, and 2 years were 66.3% and 47.5% (P = 0.0001), 31.12% and 15.9% (P = 0.0001), 21.32% and 13.64% (P = 0.033), and 2.89% and 2.27% (P = 0.78), respectively. Thus, the survival rate was significantly improved in the combination group (Table 1).
Outcomes of HIFU for pancreatic cancer (Japan)
In Japan, a study to verify the safety of HIFU for advanced un-resectable PC was reported in 2014 [39]. The results of an efficacy analysis of 30 cases showed the mean number of treatments was 2.6 (2–4), and the mean treatment time was 2.4 h (1.3–4 h). The mean number of irradiations was 2285 (110–4085), the rate of sedative administration was 0%, and the rate of analgesic administration was 3.3%. The frequency of adverse events was 10%, and there were two cases of pancreatic pseudocysts, one of which was treated with endoscopic drainage, while the other case received conservative therapy. Delayed pancreatitis occurred in one case 2 weeks after treatment. There were no serious adverse events, and the authors concluded that HIFU for advanced un-resectable PC was safe and minimally invasive (Table 1).
Further, a study of 176 cases of advanced un-resectable PC reported in 2021 [68] found that the frequency of adverse events was 2.8%, none of which was serious. Early pain relief was observed in 63.8% of cases, and the therapeutic effects on the primary lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) were complete response (CR) in 0%, partial response (PR) in 20%, stable disease (SD) in 60.2%, and progressive disease (PD) in 27.8% of cases. The tumor control rate for the primary lesion was 72.2%. Regarding treatments after HIFU therapy, open surgery for PC removal could be performed in 4.5% of un-resectable PC cases. In addition, the mean post-diagnosis survival was significantly longer in 176 patients who underwent HIFU (648 days [21.3 months]) than in 100 patients who underwent chemotherapy alone (288 days [9.5 months]) (P < 0.001). Additionally, the mean survival was significantly longer in the stage III group at 372 days (12.2 months) compared with the stage IV group at 220 days (7.2 months) (P < 0.001). Taken together, these results suggest that HIFU contributes to prolonged survival in patients with PC (Table 1).
Meta-analyses and systematic reviews of HIFU for pancreatic cancer
To date, two meta-analyses and two systematic reviews on HIFU for PC have been reported. A 2014 meta-analysis [69] included a total of 23 studies: 19 randomized controlled trials and four clinical controlled trials. Of those studies, 14 reported on safety. The 6- and 12-month survival rates, efficacy rates, and clinical efficacy rates for the HIFU radiation chemotherapy group were significantly higher than those for radiotherapy (P < 0.05), GEM monotherapy (P < 0.05), GEM + cisplatin (P < 0.05), and GEM + 5-fluorouracil (P < 0.05). There were no serious adverse events, and the most common complications were skin burns and fever.
The other systematic review from 2014 [70] reported pain relief in 66.7–100% of patients, a MST of 11.25–12.4 months, and an overall survival time of 12.6 months (95% CI 10.2–15.0). In a 2015 systematic review [71] of 136 cases of advanced local PC from five studies, pain relief was observed in 79% of patients, and the MST was 10.0–12.6 months after HIFU alone or in combination with simultaneous chemotherapy. Another meta-analysis from 2017 [72] examined the usefulness of HIFU for pain relief in 729 cases of un-resectable PC from 23 studies. The pain-relief effect was 81% (95% CI 76–86), and the authors concluded that HIFU is an effective means of pain relief in patients with advanced PC.
In a 2018 systematic review of 581 cases from 17 studies [73], the tumor response of 120 patients from six studies was described. Complete regression was observed in 14%, ≥ 75% regression in 70%, 50–75% regression in 11%, 25–50% regression in 4%, and 0–25% regression in 1% of patients. Moreover, CR was observed in 10% and 5.1% of patients in two studies and PR in 38.5–70% of patients in six studies. Additionally, pain relief was described for 148 cases from nine studies. Complete or partial relief on a visual analog scale (75–100%) was observed in 83%, 50–75% relief in 8%, and 25–50% relief in 9% of patients.
The most recent meta-analysis from 2021 [74] examined 992 cases of un-resectable PC from seven studies. Survival was longer in the combination therapy group of HIFU plus chemotherapy compared with the chemotherapy alone group, with a hazard ratio of 0.40 (95% CI 0.28–0.58). Moreover, the 1-year survival rate was significantly higher in the combination therapy group (odds ratio 0.35, 95% CI 0.22–0.53, P < 0.001).
The results of these meta-analyses and systematic reviews indicate that HIFU has antitumor and pain-relieving effects on advanced PC, though higher quality evidence is needed for clinical application. Further research using standardized and unified assessment criteria is needed.
New developments in HIFU for pancreatic cancer
HIFU has many potential uses, including relieving pain and other symptoms, promoting antitumor effects, prolonging survival, enhancing drug delivery (drug penetration), and strengthening specific immunity for cancer [11,12,13,14,15,16, 22, 27, 30, 32, 43, 62, 63]. At present, the results of various other studies are awaited, including those examining the abscopal effect from the tumor immune response [16], preoperative HIFU aimed at R0 resection for un-resectable local advanced PC for which chemotherapy or chemo-radiotherapy was successful [68], low-power cumulative HIFU therapy [75, 76], drug delivery therapies [77], and sonodynamic therapy [77].
Conclusion
HIFU is a cutting-edge therapy for PC. However, further study through animal experiments and clinical research, as well as the accumulation of more cases and improved device performance, are needed. At present, HIFU is used in combination with systemic chemotherapy to achieve local antitumor effects and pain relief in patients with un-resectable PC. Unlike radiation therapy, HIFU can be performed as many times as needed. As novel chemotherapies develop, HIFU is expected to exhibit an even greater effect on prolonging survival through synergistic effects with these new regimens. Previous clinical studies have indicated that HIFU can be performed safely to treat un-resectable PC. In future, this method could be a minimally invasive addition to treatment strategies for patients with PC with a poor prognosis.
Abbreviations
- HIFU:
-
High-intensity focused ultrasound
- PC:
-
Pancreatic cancer
- QOL:
-
Quality of life
- MST:
-
Median survival time
- US:
-
Ultrasound
- MRI:
-
Magnetic resonance imaging
- CEUS:
-
Contrast-enhanced ultrasonography
- GEM:
-
Gemcitabine
- RECIST:
-
Response Evaluation Criteria in Solid Tumors
- CR:
-
Complete response
- PR:
-
Partial response
- SD:
-
Stable disease
- PD:
-
Progressive disease
References
World Health Organization. World Health Statistics, 2020. WHO: Geneva, Switzerland. Available from: https://www.who.int/data/gho/publications/world-health-statistics.
Dubinsky TJ, Cuevas C, Dighe MK, et al. High-intensity focused ultrasound: current potential and oncologic applications. AJR Am J Roentgenol. 2008;190:191–9.
Hwang JH, Wang YN, Warren C, et al. Preclinical in vivo evaluation of an extracorporeal HIFU device for ablation of pancreatic tumors. Ultrasound Med Biol. 2009;35:967–75.
Sofuni A, Moriyasu F, Sano T, et al. The current potential of high-intensity focused ultrasound for pancreatic carcinoma. J Hepatobil Pancreat Sci. 2011;18:295–303.
Japanese Society of Ultrasonics, Instrument and Safety Committee. Materials related to the safety of ultrasonic diagnostic equipment. Japanese Society of Ultrasonics. 2009:4–28.
World Federation for Ultrasound in Medicine and Biology (WFUMB). Synopsis. Ultrasound Med Biol. 1992;18:733–7.
Xie B, Li YY, Jia L, et al. Experimental ablation of the pancreas with high intensity focused ultrasound (HIFU) in a porcine model. Int J Med Sci. 2010;8:9–15.
Jiang L, Hu B, Guo Q, et al. Treatment of pancreatic cancer in a nude mouse model using high-intensity focused ultrasound. Exp Ther Med. 2013;5:39–44.
Hassanuddin A, Choi JH, Seo DW, et al. Factors affecting tumor ablation during high intensity focused ultrasound treatment. Gut Liver. 2014;8:433–7.
Dupré A, Melodelima D, Pflieger H, et al. Thermal ablation of the pancreas with intraoperative high-intensity focused ultrasound: safety and efficacy in a porcine model. Pancreas. 2017;46:219–24.
Wang RS, Liu LX, Gu YH, et al. The effect of endostatin and gemcitabine combined with HIFU on the animal xenograft model of human pancreatic cancer. Biomed Pharmacother. 2010;64:309–12.
Lee ES, Lee JY, Kim H, et al. Pulsed high-intensity focused ultrasound enhances apoptosis of pancreatic cancer xenograft with gemcitabine. Ultrasound Med Biol. 2013;39:1991–2000.
Kim JH, Kim H, Kim YJ, et al. Dynamic contrast-enhanced ultrasonographic (DCE-US) assessment of the early response after combined gemcitabine and HIFU with low-power treatment for the mouse xenograft model of human pancreatic cancer. Eur Radiol. 2014;24:2059–68.
Li T, Chen H, Khokhlova T, et al. Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors. Ultrasound Med Biol. 2014;40:1523–34.
Yu MH, Lee JY, Kim HR, et al. Therapeutic effects of microbubbles added to combined high-intensity focused ultrasound and chemotherapy in a pancreatic cancer xenograft model. Korean J Radiol. 2016;17:779–88.
Wang X, Sun J. High-intensity focused ultrasound in patients with late-stage pancreatic carcinoma. Chin Med J (Engl). 2002;115:1332–5.
Xie DR, Chen D, Teng H. A multicenter non-randomized clinical study of high intensity focused ultrasound in treating patients with local advanced pancreatic carcinoma. Zhongguo Zhongliu Linchuang. 2003;30:630–4.
Xu YQ, Wang GM, Gu YZ, et al. The acesodyne effect of high intensity focused ultrasound on the treatment of advanced pancreatic carcinoma. Zhongguo Linchuang Yixue (Chinese). 2003;10:322–3.
Yuan C, Yang L, Yao C. Observation of high intensity focused ultrasound treating 40 cases of pancreatic cancer. Linchuang Gandanbing Zazhi (Chinese). 2003;19:145–6.
Wu F, Wang ZB, Zhu H, et al. Feasibility of US-guided high-intensity focused ultrasound treatment in patients with advanced pancreatic cancer: initial experience. Radiology. 2005;236:1034–40.
Xiong LL, Hwang JH, Huang XB, et al. Early clinical experience using high intensity focused ultrasound for palliation of inoperable pancreatic cancer. JOP. 2009;10:123–9.
Zhao H, Yang G, Wang D, et al. Concurrent gemcitabine and high-intensity focused ultrasound therapy in patients with locally advanced pancreatic cancer. Anti Cancer Drugs. 2010;21:447–52.
Jung SE, Cho SH, Jang JH, et al. High-intensity focused ultrasound ablation in hepatic and pancreatic cancer: complications. Abdom Imaging. 2011;36:185–95.
Orsi F, Zhang L, Arnone P, et al. High-intensity focused ultrasound ablation: effective and safe therapy for solid tumors in difficult locations. AJR Am J Roentgenol. 2010;195:W245–52.
Orsi F, Arnone P, Chen W, et al. High intensity focused ultrasound ablation: a new therapeutic option for solid tumors. J Cancer Res Ther. 2010;6:414–20.
Orgera G, Monfardini L, Della Vigna P, et al. High-intensity focused ultrasound (HIFU) in patients with solid malignancies: evaluation of feasibility, local tumour response and clinical results. Radiol Med. 2011;116:734–48.
Zhu X, Meng Z, Chen Z, et al. Metastatic adenocarcinoma of the epididymis from pancreatic cancer successfully treated by chemotherapy and high-intensity focused ultrasound therapy: a case report and review of the literature. Pancreas. 2011;40:1160–2.
Sung HY, Jung SE, Cho SH, et al. Long-term outcome of high-intensity focused ultrasound in advanced pancreatic cancer. Pancreas. 2011;40:1080–6.
Wang K, Chen Z, Meng Z, et al. Analgesic effect of high intensity focused ultrasound therapy for unresectable pancreatic cancer. Int J Hyperth. 2011;27:101–7.
Lee JY, Choi BI, Ryu JK, et al. Concurrent chemotherapy and pulsed high-intensity focused ultrasound therapy for the treatment of unresectable pancreatic cancer: initial experiences. Korean J Radiol. 2011;12:176–86.
Khokhlova TD, Hwang JH. HIFU for palliative treatment of pancreatic cancer. J Gastrointest Oncol. 2011;2:175–84.
Yuan Y, Shen H, Hu XY, et al. Multidisciplinary treatment with chemotherapy, targeted drug, and high-intensity focused ultrasound in advanced pancreatic carcinoma. Med Oncol. 2012;29:957–61.
Wang K, Chen L, Meng Z, et al. High intensity focused ultrasound treatment for patients with advanced pancreatic cancer: a preliminary dosimetric analysis. Int J Hyperth. 2012;28:645–52.
Li PZ, Zhu SH, He W, et al. High-intensity focused ultrasound treatment for patients with unresectable pancreatic cancer. Hepatobiliary Pancreat Dis Int. 2012;11:655–60.
Wang K, Zhu H, Meng Z, et al. Safety evaluation of high-intensity focused ultrasound in patients with pancreatic cancer. Onkologie. 2013;36:88–92.
Ge HY, Miao LY, Wang JR, et al. Correlation Between ultrasound reflection intensity and tumor ablation ratio of late-stage pancreatic carcinoma in HIFU Therapy: dynamic observation on ultrasound reflection intensity. Sci World J. 2013;2013:852874.
Gao HF, Wang K, Meng ZQ, et al. High intensity focused ultrasound treatment for patients with local advanced pancreatic cancer. Hepatogastroenterology. 2013;60:1906–10.
Xiaoping L, Leizhen Z. Advances of high intensity focused ultrasound (HIFU) for pancreatic cancer. Int J Hyperth. 2013;29:678–82.
Sofuni A, Moriyasu F, Sano T, et al. Safety trial of high-intensity focused ultrasound therapy for pancreatic cancer. World J Gastroenterol. 2014;20:9570–7.
Zhou Y. High-intensity focused ultrasound treatment for advanced pancreatic cancer. Gastroenterol Res Pract. 2014;2014:205325.
Ge HY, Miao LY, Xiong LL, et al. High-intensity focused ultrasound treatment of late-stage pancreatic body carcinoma: optimal tumor depth for safe ablation. Ultrasound Med Biol. 2014;40:947–55.
Wu F. High intensity focused ultrasound: a noninvasive therapy for locally advanced pancreatic cancer. World J Gastroenterol. 2014;20:16480–8.
Dimitrov D, Andreev T, Feradova H, et al. Multimodality treatment by FOLFOX plus HIFU in a case of advanced pancreatic carcinoma: a case report. JOP. 2015;16:66–9.
Luo J, Ren X, Yu T. Efficacy of extracorporeal ultrasound-guided high intensity focused ultrasound: an evaluation based on controlled trials in china. Int J Radiat Biol. 2015;91:480–5.
Vidal-Jove J, Perich E, Del Castillo MA. Ultrasound guided high intensity focused ultrasound for malignant tumors: the Spanish experience of survival advantage in stage III and IV pancreatic cancer. Ultrason Sonochem. 2015;27:703–6.
Shi Y, Ying X, Hu X, et al. Influence of high intensity focused ultrasound (HIFU) treatment to the pancreatic function in pancreatic cancer patients. Pak J Pharm Sci. 2015;28:1097–100.
Wang G, Zhou D. Preoperative ultrasound ablation for borderline resectable pancreatic cancer: a report of 30 cases. Ultrason Sonochem. 2015;27:694–702.
Copelan A, Hartman J, Chehab M, et al. High-intensity focused ultrasound: current status for image-guided therapy. Semin Intervent Radiol. 2015;32:398–415.
Khokhlova TD, Hwang JH. HIFU for palliative treatment of pancreatic cancer. Adv Exp Med Biol. 2016;880:83–95.
Marinova M, Rauch M, Mücke M, et al. High-intensity focused ultrasound (HIFU) for pancreatic carcinoma: evaluation of feasibility, reduction of tumour volume and pain intensity. Eur Radiol. 2016;26:4047–56.
Li YJ, Huang GL, Sun XL, et al. The combination therapy of high-intensity focused ultrasound with radiotherapy in locally advanced pancreatic carcinoma. World J Surg Oncol. 2016;14:60.
Li X, Wang K, Zheng L, et al. Retrospective analysis of high intensity focused ultrasound combined with S-1 in the treatment of metastatic pancreatic cancer after failure of gemcitabine. Am J Cancer Res. 2016;6:84–90.
Strunk HM, Henseler J, Rauch M, et al. Clinical use of high-intensity focused ultrasound (HIFU) for tumor and pain reduction in advanced pancreatic cancer. RoFo. 2016;188:662–70.
Ning ZY, Cheng CS, Xie J, et al. A retrospective analysis of survival factors of high intensity focused ultrasound (HIFU) treatment for unresectable pancreatic cancer. Discov Med. 2016;21:435–45.
Niu S, Cheng L, Qiao Y, et al. Combined stent insertion and high-intensity focused ultrasound ablation for patients with malignant obstructive jaundice. Surg Laparosc Endosc Percutan Tech. 2016;26:488–92.
Strunk HM, Lützow C, Henseler J, et al. Mesenteric vessel patency following HIFU therapy in patients with locally invasive pancreatic cancer. Ultraschall Med. 2018;39:650–8.
Ji Y, Zhang Y, Zhu J, et al. Response of patients with locally advanced pancreatic adenocarcinoma to high-intensity focused ultrasound treatment: a single-center, prospective, case series in China. Cancer Manag Res. 2018;10:4439–46.
Marinova M, Huxold HC, Henseler J, et al. Clinical effectiveness and potential survival benefit of US-guided high-intensity focused ultrasound therapy in patients with advanced-stage pancreatic cancer. Ultraschall Med. 2019;40:625–37.
Marinova M, Wilhelm-Buchstab T, Strunk H. Advanced pancreatic cancer: high-intensity focused ultrasound (HIFU) and other local ablative therapies. RoFo. 2019;191:216–27.
Ning Z, Xie J, Chen Q, et al. HIFU is safe, effective, and feasible in pancreatic cancer patients: a monocentric retrospective study among 523 patients. OncoTargets Ther. 2019;12:1021–9.
Zhu B, Li J, Diao L, et al. High-intensity focused ultrasound ablation for advanced pancreatic cancer. J Cancer Res Ther. 2019;15:831–5.
Tao SF, Gu WH, Gu JC, et al. A retrospective case series of high-intensity focused ultrasound (HIFU) in combination with gemcitabine and oxaliplatin (Gemox) on treating elderly middle and advanced pancreatic cancer. OncoTargets Ther. 2019;12:9735–45.
Sofuni A, Fujita M, Asai Y, et al. A case of unresectable pancreatic cancer with long-term survival in high-intensity focused ultrasound (HIFU) therapy. Ultrasound Int Open. 2019;5:E89-92.
Yang SY, Liu F, Liu Y, et al. stent insertion with high-intensity focused ultrasound ablation for distal biliary obstruction secondary to pancreatic carcinoma. Med Baltim. 2020;99: e19099.
Dimitrov D, Stanislavova N, Yotsov T, et al. Recurrent pancreatic cancer patient treated by chemotherapy and focused ultrasound surgery. A case report. Med Ultrason. 2020;22:247–9.
Guo X, Zhu H, Zhou K, et al. Effects of high-intensity focused ultrasound treatment on peripancreatic arterial and venous blood vessels in pancreatic cancer. Oncol Lett. 2020;19:3839–50.
Thudium M, Bette B, Tonguc T, et al. Multidisciplinary management and outcome in pancreatic cancer patients treated with high-intensity focused ultrasound. Int J Hyperth. 2020;37:456–62.
Sofuni A, Asai Y, Tsuchiya T, et al. Novel therapeutic method for unresectable pancreatic cancer-the impact of the long-term research in therapeutic effect of high-intensity focused ultrasound (HIFU) therapy. Curr Oncol. 2021;28:4845–61.
Li CC, Wang YQ, Li YP, et al. High-intensity focused ultrasound for treatment of pancreatic cancer: a systematic review. J Evid Based Med. 2014;4:270–81.
Keane MG, Bramis K, Pereira SP, et al. Systematic review of novel ablative methods in locally advanced pancreatic cancer. World J Gastroenterol. 2014;20:2267–78.
Rombouts SJ, Vogel JA, van Santvoort HC, et al. Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg. 2015;102:182–93.
Dababou S, Marrocchio C, Rosenberg J, et al. A meta-analysis of palliative treatment of pancreatic cancer with high intensity focused ultrasound. J Ther Ultrasound. 2017;5:9.
Saccomandi P, Lapergola A, Longo F, et al. Thermal ablation of pancreatic cancer: a systematic literature review of clinical practice and pre-clinical studies. Int J Hyperth. 2018;35:398–418.
Guo J, Wang Y, Chen J, et al. Systematic review and trial sequential analysis of high-intensity focused ultrasound combined with chemotherapy versus chemotherapy in the treatment of unresectable pancreatic ductal adenocarcinoma. Int J Hyperthermia. 2021;38:1375–83.
Zhao J, Zhao F, Shi Y, et al. The efficacy of a new high intensity focused ultrasound therapy for locally advanced pancreatic cancer. J Cancer Res Clin Oncol. 2017;143:2105–11.
Zhao J, Shen H, Hu X, et al. The efficacy of a new high-intensity focused ultrasound therapy for metastatic pancreatic cancer. Int J Hyperthermia. 2021;38:288–95.
Horise Y, Maeda M, Konishi Y, et al. Sonodynamic therapy with anticancer micelles and high-intensity focused ultrasound in treatment of canine cancer. Front Pharmacol. 2019;10:545.
Acknowledgements
We would like to thank Toshihiko Saito, Fuminori Moriyasu, Takatomo Sano, and Mitsuru Fujita of Tokyo Medical University. We would also like to thank Editage (www.editage.com) for English language editing.
Author information
Authors and Affiliations
Contributions
Conceptualization, AS; data curation, AS, YA, MS, KY; investigation, AS, YA, MS, KY; supervision, TI; validation, AT, TI; writing—original draft, AS; writing, review, and editing, AS. All authors have read and agreed to the published version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
Atsushi Sofuni, Yasutsugu Asai, and Takao Itoi declare that they have no conflicts of interest.
Ethical approval
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients for being included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.
About this article
Cite this article
Sofuni, A., Asai, Y., Mukai, S. et al. High-intensity focused ultrasound therapy for pancreatic cancer. J Med Ultrasonics (2022). https://doi.org/10.1007/s10396-022-01208-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10396-022-01208-4