Objective To evaluate the safety and efficacy of high intensity focused ultrasound for palliation of inoperable pancreatic cancer in humans. Patients Eighty-nine patients with advanced pancreatic cancer were treated with high intensity focused ultrasound. Methods Pain relief, local tumor control rate, median survival and complications were observed after high intensity focused ultrasound treatment. Pain relief was achieved in The median survival was Twoyear survival rate was as follows: stage II,
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Objective To evaluate the safety and efficacy of high intensity focused ultrasound for palliation of inoperable pancreatic cancer in humans. Patients Eighty-nine patients with advanced pancreatic cancer were treated with high intensity focused ultrasound. Methods Pain relief, local tumor control rate, median survival and complications were observed after high intensity focused ultrasound treatment. Pain relief was achieved in The median survival was Twoyear survival rate was as follows: stage II, Complications included superficial skin burns 3.
There were no severe complications or adverse events related to high intensity focused ultrasound therapy seen in any of the patients treated. Conclusions Although this retrospective study has significant limitations, preliminary results suggest that the clinical application of high intensity focused ultrasound for pancreatic cancer appears to be safe and is a promising modality of treatment for palliation of pain related to pancreatic cancer.
A majority of patients diagnosed with pancreatic cancer have advanced disease at the time of diagnosis and are not amenable for surgery with intent to cure. The prognosis of patients with pancreatic cancer is one of the worst among all cancers. Pain control is an important component of palliation and is commonly performed using opioid therapy and celiac plexus neurolysis.
Opioid narcotics have undesired side-effects ranging from mild constipation to respiratory depression and altered mental status. Celiac plexus neurolysis can be performed in patients who have severe intractable pain that is poorly controlled on opioids; however, the procedure is invasive, requiring endoscopic ultrasound or CT-guidance.
High intensity focused ultrasound HIFU ablation is a non-invasive method of ablation therapy using focused ultrasound energy from an extracorporeal source that is targeted within the body resulting in thermally induced necrosis and apoptosis [ 6 , 7 , 8 ]. HIFU, also termed focused ultrasound surgery, is delivered from an ultrasound transducer that is focused either mechanically spherically curved or using a focusing lens or electronically by phasing an array of transducers.
The focal characteristics of most clinically available transducers are similar to a grain of rice. The acoustic intensities used in HIFU differ from diagnostic ultrasound in that the time averaged acoustic intensity at the focus is several orders of magnitude greater for HIFU. Acoustic energy is absorbed and heat is generated by delivering high acoustic intensities to tissue. Because of focusing, the acoustic intensities are high only within the focal region; however, outside the focal region the acoustic intensities are substantially lower, minimizing the risk of unintended injury to tissue outside the focal region.
This has been seen in patients treated with HIFU followed by surgical resection [ 8 ]. As the lesion evolves the cells degenerate resulting in coagulative necrosis; however, this effect is significant for the treatment of the pancreas where cell lysis has potential to release autodigestive enzymes and lead to pancreatitis. With HIFU treatments that result in thermal fixation, pancreatic cells do not undergo lysis until the intracellular enzymes have been completely denatured and inactivated, theoretically reducing the risk of pancreatitis with HIFU therapy.
Although the majority of the initial cell death within a high intensity ultrasound field is due to cell necrosis from thermal injury, high intensity ultrasound can also induce apoptosis. The primary mechanism of cell death from hyperthermia is due to apoptosis [ 7 ]. The procedure requires no incisions or needle punctures and is often performed without sedation [ 9 ]. An illustration of how HIFU therapy is administered for ablation of pancreatic tumors is provided in Figure 1.
HIFU therapy has been undergoing rapid development over the last decade such that several clinical HIFU devices are now commercially available. There are several reports in the literature describing the use of HIFU for treatment of pancreatic cancer, cholangiocarcinoma, hepatocellular carcinoma, metastatic liver disease, prostate cancer, breast cancer, renal cell carcinoma, osteosarcoma, uterine fibroids and other various solid tumors [ 10 , 11 , 12 , 13 , 14 ].
Figure 1. High intensity focused ultrasound treatment is non-invasive using a transducer that is located above the patient that is in the supine position. Reproduced with permission . The use of HIFU for the palliative treatment of pancreatic cancer may be useful in patients that develop symptoms that would benefit from local tumor control. Subsequently, there have been several additional case-series and non-randomized studies, primarily published in the Chinese literature, reporting similar findings of safety and pain relief with some studies even suggesting a survival benefit [ 9 , 16 , 17 , 18 , 19 , 20 , 21 ].
To date there is a single small case series of 8 patients in the English literature reporting the use of extracorporeal HIFU to treat pancreatic cancer [ 14 ].
All 8 patients had pain related to pancreatic cancer prior to initiating HIFU therapy with all patients obtaining relief of pain symptoms within 48 hours following HIFU therapy. The authors reported no skin burns, tumor hemorrhage, large blood vessel rupture, bowel perforation, or pancreatitis following HIFU therapy.
HIFU has been used clinically in China since to treat over 20, patients for a wide range of indications with an excellent safety profile. Clinical results from China suggests that HIFU may be an alternative treatment for patients with locally advanced disease [ 9 , 13 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].
Patients were all considered to have inoperable pancreatic cancer confirmed by an experienced pancreatic surgeon. The criteria for unresectability included evidence of distant metastatic disease, imaging evidence CT, MRI or endoscopic ultrasound of involvement of the celiac trunk or superior mesenteric artery, significant medical comorbidities that precluded these patients from an attempt at surgical resection, or refusal to undergo surgery.
Patients were also allowed to continue chemotherapy or radiation therapy while undergoing HIFU therapy. Out of the 89 patients 56 Tumors were located in the pancreatic head in 34 patients Twenty-six Four patients 4. Five patients 5. The other 45 patients It is composed of four subsystems: 1 treatment table; 2 water degassing system; 3 diagnostic B-mode ultrasound imaging system GE Logiq 5, Seongnam, Korea with an imaging transducer mounted coaxially to the HIFU transducer; and 4 the HIFU transducer Figure 3 , which is a fixed focus concave transducer composed of multiple piezoelectric ceramics having an overall aperture of 37 cm with a focal length of 26 cm.
The elements of the HIFU transducer are driven in phase at a frequency of 1. The -6 dB focal dimensions are 8 mm in length and 3 mm in diameter. Figure 2. Components include a treatment table with upper and lower high intensity focused ultrasound transducers A , B-mode ultrasound imaging system B , and computer control system C. In addition, there is an electrical power system and water treatment system not pictured. Reproduced with permission Yuande Biomedical Engineering Corp.
Figure 3. The transducer is made of individual piezoceramic elements and is concave with a geometric focus of 26 cm. The center hole in the transducer is for the ultrasound imaging probe. The water bladder was filled with degassed water and coupled to the skin with ultrasound coupling gel. The tumor target was identified with the B-mode ultrasound imaging transducer, and the treatment plan was determined. HIFU treatment was delivered using the spot accumulation method where individual spots are treated in an overlapping fashion to treat a volume of tissue Figure 4.
Anesthesia was not administered to any of the patients. The patients fasted beginning the night before a HIFU procedure and the placement of a nasogastric tube was required prior to two HIFU treatment sessions in order to remove gas from the stomach that was obscuring the tumor.
The therapy was divided into several sessions such that each treatment session was approximately 60 minutes. The treatment of an entire tumor volume required sessions to complete therapy. Figure 4. The spot accumulation method of high intensity focused ultrasound treatment. Treatment spots are placed in an overlapping fashion.
The interval spacing in the x-y plane is mm. The interval spacing in the z direction is mm. Pain response and complications were observed after completion of HIFU treatments and at one month posttreatment. Pain response was routinely assessed during follow-up visits using a numeric pain scale Contrast enhanced CT or MRI was used to determine the objective tumor response and to assess for any evidence of ablation absence of perfusion on imaging.
Mean, median, standard deviation SD , range, and frequencies were used as descriptive statistics. Survivals were evaluated by means of the Kaplan-Meir method.
This is a retrospective study of treatment results using an approved medical device. Informed written consent for treatment was obtained from each patient and the study protocol conforms to the ethical guidelines of the "World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects" adopted by the 18th WMA General Assembly, Helsinki, Finland, June , as revised in Tokyo , as reflected in a priori approval by the ethics review committee.
There were no patients who had a complete response, A partial ablation was achieved in 30 patients Figure 5. Contrast enhanced-CT scan of a year-old female demonstrating a tumor in the body of the pancreas prior to high intensity focused ultrasound therapy a. Figure 6. Contrast enhanced-CT scan of a year-old male demonstrating a tumor in the body of the pancreas prior to high intensity focused ultrasound therapy a. Figure 7. A CT scan made before high intensity focused ultrasound demonstrating a tumor in the head of the pancreas.
A CT scan demonstrating no significant change one month following high intensity focused ultrasound treatment. All four images are taken from the same patient. Sixty-seven patients Pain was relieved in 54 patients The complete remission of pain 0 pain score and no need for opioid analgesics was observed in 21 patients Pain relief was observed in The median survival for stage II was The median survival for stage III was The overall median survival was 8.
The survival rate at 2 years was as follows: stage II, There were 3 patients 3. There were 6 patients 6. There was one patient 1. The patient was asymptomatic and was treated with somatostatin for one week.
HIFU for palliative treatment of pancreatic cancer
Current therapies are ineffective, and the treatment of patients with advanced disease is palliative. In the past decade, HIFU ablation has emerged as a modality for palliative treatment of pancreatic tumors. Multiple preclinical and non-randomized clinical trials have been performed to evaluate the safety and efficacy of this procedure. Substantial tumor-related pain reduction was achieved in most cases after HIFU treatment and few significant side effects were observed.
A meta-analysis of palliative treatment of pancreatic cancer with high intensity focused ultrasound
If a patient develops gastric-outlet obstruction, treatment may include duodenal wall stents or percutaneous endoscopic gastrostomy placement for decompression. Occasionally, a patient may need surgery to create a bypass biliary bypass or gastric bypass to manage obstructive jaundice and gastric outlet obstruction. The majority of patients diagnosed with pancreatic cancer already present metastatic disease or they later develop metastatic disease. This is mainly in the liver and peritoneal cavity. This type of pain is multi-factorial and may be caused by infiltration of nerve sheaths and neural ganglia, increased ductal and interstitial pressure, and gland inflammation Staatas et al. The current management of pancreatic pain starts with non-opioid analgesics, such as nonsteroidal anti-inflammatory drugs NSAIDs , and progresses to increasing doses of opioid analgesics.
HIFU for Palliative Treatment of Pancreatic Cancer
Pancreatic cancer is under high mortality but has few effective treatment modalities. High-intensity focused ultrasound HIFU is becoming an emerging approach of noninvasively ablating solid tumor in clinics. A variety of solid tumors have been tried on thousands of patients in the last fifteen years with great success. The principle, mechanism, and clinical outcome of HIFU were introduced first. All clinical cases of HIFU treatment for the advanced pancreatic cancer alone or in combination with chemotherapy or radiotherapy in published papers were reviewed and summarized for its efficacy, pain relief, clinical benefit rate, survival, Karnofsky performance scale KPS score, changes in tumor size, occurrence of echogenicity, serum level, diagnostic assessment of outcome, and associated complications. Immune response induced by HIFU ablation may become an effective way of cancer treatment. Comments for a better outcome and current challenges of HIFU technology are also covered.