Hepatobiliary Pancreat Dis Int，Vol 11，No 6 • December 15，2012 • www.hbpdint.com • 655
Author Affiliations: Department of General Surgery (Li PZ, Zhu
SH, Zhu LY, Liu SP, Liu Y, Wang GH and Ye F), and Department of
Radiology (He W), Third Xiangya Hospital, Central South University,
Changsha 410013, China
Corresponding Author: Shai-Hong Zhu, MD, PhD, Department of
General Surgery, Third Xiangya Hospital, Central South University,
Changsha 410013, China (Tel: 86-731-88618034; Fax: 86-731-88618034;
© 2012, Hepatobiliary Pancreat Dis Int. All rights reserved.
BACKGROUND: High-intensity focused ultrasound (HIFU)
is a non-invasive method of solid tissue ablation therapy.
However, only a few studies have reported the effect of HIFU for
unresectable pancreatic cancer. This study aimed to evaluate
the clinical benefits, survival time and complications associated
with the use of HIFU ablation in patients with unresectable
METHODS: Twenty-five patients with unresectable pancreatic
cancer were enrolled in our study. All patients received HIFU
therapy for tumors at least once. The therapeutic effects of HIFU
was evaluated in terms of Karnofsky performance status (KPS)
scores, pain relief, serum CA19-9, and imaging by B-US and CT
before and after the therapy. We also recorded median overall
survival time and complications caused by the treatment.
RESULTS: In the 25 patients, KPS scores were above 60, and
increased KPS was observed in 23 patients after treatment.
Pain relief occurred in 23 patients. Serum CA19-9 levels were
significantly reduced one month after HIFU treatment and
became negative in 5 patients. B-US revealed enhanced tumor
echogenicity in 13 patients and decreased tumor blood supply
in 9. Tumor necrosis was confirmed by CT in 8 patients one
month after HIFU treatment. The median overall survival time
was 10 months, and the 1-year survival rate was 42%. No severe
complications were observed after HIFU treatment.
CONCLUSION: HIFU can effectively relieve pain, increase KPS,
decrease tumor growth and prolong the survival time of patients
with unresectable pancreatic cancer.
(Hepatobiliary Pancreat Dis Int 2012;11:655-660)
KEY WORDS: pancreatic cancer;
high-intensity focused ultrasound;
survival time of the patient is only 3-5 months.[1, 2]
Currently, surgical resection is considered the best
choice for such patients seeking long-term survival,
but 60%-70% of patients with pancreatic cancer are
ineligible for surgery because of metastatic or locally
advanced cancer. In patients with no surgical option,
their quality of life is influenced by cancer-related
pain. Therefore, the improvement of the quality of
life must be attempted in patients with unresectable
High-intensity focused ultrasound (HIFU) is considered
a non-invasive technique for ablation therapy of solid
tissue. It produces a thermal and cavitational effect at
high intensities to induce necrosis and apoptosis in a
target region of the tumor.[4, 5] HIFU has been used as a
therapeutic option for prostatic carcinoma in the United
States and Europe, and studies[1, 6] have reported its
long-term effect in treatment of patients with pancreatic
cancer. This study aimed to evaluate the long-term effect
of HIFU in patients with unresectable pancreatic cancer.
ancreatic cancer produces the worst outcomes
among all malignant tumors. Its one-year survival
rate is estimated to be <10% and the median
Twenty-five patients with unresectable pancreatic
cancer who received HIFU treatment at our hospital
between November 2006 and November 2009 were
enrolled in the study. Inclusion criteria included
evidence of pancreatic cancer confirmed pathologically
Original Article / Pancreas
High-intensity focused ultrasound treatment for
patients with unresectable pancreatic cancer
Peng-Zhou Li, Shai-Hong Zhu, Wei He, Li-Yong Zhu, Sheng-Ping Liu,
Yan Liu, Guo-Hui Wang and Fei Ye
Hepatobiliary & Pancreatic Diseases International
656 • Hepatobiliary Pancreat Dis Int，Vol 11，No 6 • December 15，2012 • www.hbpdint.com
or diagnosed by CT or PET/CT and serum analysis;
presence of inoperable pancreatic cancer and refusal
to undergo surgery or other treatment; and minimum
diameter of a solid tumor (≥1.0 cm). Exclusion criteria
included intolerance to HIFU treatment; radiation or
chemotherapy administered in the last 3 months; and
life expectancy <3 months. The study was conducted
in compliance with the protocol approved by the
Institutional Review Board and/or Investigational Ethics
Committee of Third Xiangya Hospital, Central South
University, and informed consent was provided by all
YDME FEP-BY02 High-Intensity Focused Ultrasound
Tumor Therapeutic Equipment (Yuande Bio-Medical
Engineering, Beijing, China) was used. This HIFU
model has been previously described in detail. The
HIFU transducer is made of 251 individual PZT (lead
zirconate titanate) crystal elements that are driven in
phase at 1 MHz. It has an integrated B-US imaging
probe (Logiq 5, GE Healthcare, Seongnam, Korea), an
aperture of 37 cm, and a focal distance of 25.5 cm. The
focus has a 6 dB beam width of 1.6 mm and an axial
length of 10 mm. HIFU treatment is delivered using a
computer program that allows the operator to identify
the target region. When necessary, the operator can
also specify the electrical power delivered to the HIFU
transducer, the pulse length, the duty factor, the interval
spacing between treatment sites and the number of
pulses per treatment site. In addition, there is an
electrical power system to drive the HIFU transducer
and a water-treatment system that vacuum-degasses
The main parameters of the equipment for treatment
included input power, 400-1000 W (input power varied
depending on depth of tumor); effective therapy depth,
2-15 cm; pulse length, 300-400 msec with a duty factor
of 40%-50%; unit transmit time (t1), 150-200 msec;
intermission time (t2), 150-200 seconds; and treatment
times of 30-50 seconds at each location. All parameters
were adjusted according to tumor depth. All patients
were imaged with integrated B-US prior to the HIFU
treatment, which was carried out automatically. Only
when the target tumor and its adjacent tissues could be
clearly identified in the B-US, was the treatment carried
out. HIFU ablation was based on elementary ablated-
dot (the limited volume of tissue destroyed in a single
exposure). The ablation from dots to lines, from lines
to planes, and then from planes to volume was designed
as the algorithm of HIFU ablation.[7, 8] In this study,
with the assistance of the monitoring transducer and
computerized software, conventional B-US imaging
of the target tumor was predetermined plane-by-plane
before HIFU ablation. The tumor margin was strictly
outlined using the software supplied with the HIFU
Before HIFU therapy, patient preparation included:
history, physical examination, performance status
score, pain response, laboratory examination and tumor
imaging. The Karnofsky performance status (KPS) score
(0-100) was used. Pain response used a numeric rating
scale (0-10). Laboratory tests covered complete blood
count, urinalysis, serum chemistry, amylase, CA19-9,
chest X-ray and electrocardiogram. Tumor imaging was
performed using B-US and CT. All patients had a liquid-
only diet beginning 3 days before the HIFU treatment.
The intestinal cavity was cleansed the night before the
treatment. A nasogastric tube was used to remove gas
from the stomach.
At treatment, patients were not anesthetized. After
the patient laid on the treatment table, the B-US imaging
transducer was used to identify the tumor target and
input the treatment parameters according to its depth
and size. The HIFU system then began the treatment
controlled by the computer. Each treatment session
lasted <60 minutes, and treatments were conducted
twice a week. The treatment continued until the entire
tumor region was covered at least once.
the treatment were performed to evaluate HIFU
complications. We made the following examinations
involving complete blood count, urinalysis, serum
chemistry, amylase, chest X-ray, and electrocardiogram.
The clinical benefits of HIFU were assessed using
the performance status score, pain response, CA19-9
(positive≥37 U/mL, negative<37 U/mL) and tumor
imaging by B-US or CT as indicators after HIFU
treatment. The survival time was defined as the time
after HIFU treatment to the date of death.
examinations each week after
Data were analyzed using SPSS version 13.0 for
Windows. Mean, median, range and frequency were
taken as descriptive statistics. Before and after HIFU
treatment, KPS, pain score and serum CA19-9 were
compared using a paired t test. The rate of remission
HIFU for unresectable pancreatic cancer
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and the effectiveness were determined by the Chi-square
test. Survival time was evaluated using the Kaplan-Meier
method. A P value <0.05 was considered statistically
All the 25 patients (14 males and 11 females) were
followed up from the date of HIFU treatment until their
death. Their average age was 59.6±10.6 years (range
32-89). Tumors were located in the pancreatic head in
7 patients and in the pancreatic body and/or tail in 18.
Twelve patients had stage III pancreatic cancer, and 13
had stage IV. KPS score in all patients ranged from 60 to
80 (67.8±9.4). Twenty-four patients had positive CA19-9
tests (range 37-20 000 U/mL, mean 4635.6±2165.4). All
patients had abdominal and back pain. None of the
patients received adjuvant therapy during the follow-
up period. Six patients who had recently received
chemotherapy had HIFU treatment delayed by three
months to exclude any possible effects of chemotherapy.
All the 25 patients received a total of 31 HIFU
treatments. Nineteen patients received one treatment
session, and 6 received two sessions because their
tumors were too large to treat by one attempt. The
average number of treatment sessions was 1.2 per
patient; the mean power was 586±78.4 W; the mean
t1 was 183.3±14.6 msec; the mean t2 was 166.6±10.1
msec; the mean treatment time at each location was
45.3±5.2 seconds. One month after HIFU, 23 patients
had an enhanced KPS, and 2 showed no change (Table
1). The average KPS score was 79.8±6.7 after HIFU
treatment, which was significantly different from the
pre-HIFU KPS. CA19-9 concentrations were significantly
reduced after one month of treatment, and 5 patients
(20%) became CA19-9 negative. The average CA19-9
concentration was 3271.1±1654.3 U/mL after treatment,
Fig. 1. All images are from the same patient. A: B-US tumor image before HIFU treatment. D: B-US tumor image after HIFU treatment
shows hyper-echoic changes in the treated area. B: B-US image of tumor blood supply before HIFU treatment. E: B-US image showing
decreased tumor blood supply after HIFU treatment. C: CT image of a tumor before HIFU treatment. F: CT showing HIFU ablation.
Table 1. Characteristics of patients before and after HIFU treatment
Pre-HIFU (n, %)
90 0 (0)
80 3 (12)
70 10 (40)
60 12 (48)
Negative 1 (4)
Post-HIFU (n, %)
Table 2. Pain relief after HIFU treatment (n, %)
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658 • Hepatobiliary Pancreat Dis Int，Vol 11，No 6 • December 15，2012 • www.hbpdint.com
which was decreased more significantly than the pre-
HIFU concentration. Data on pain relief one week after
treatment are shown in Table 2. Eleven patients (44%)
had complete pain relief, and 12 (48%) had partial relief.
The total effective incidence of pain relief was 92%, and
the average pain score was reduced after HIFU treatment
(4.6±2.1 vs 2.2±0.9, P<0.05). All patients received B-US
or CT 1-3 months after last HIFU treatment. B-US
results showed enhanced echoes in 13 patients (52%)
and a decreased tumor blood supply in 9 (36%). The
Chi-square test showed that there was a significant
reduction compared to that before HIFU treatment.
Tumor necrosis was confirmed by CT in 8 patients (32%)
at one month after HIFU treatment (P<0.05), and 13
patients (52%) showed tumor reduction or no change in
tumor size after 3 months (Fig. 1). The effectiveness of
HIFU treatment was defined by the following: enhanced
echoes and a decreased tumor blood supply shown by
B-US; tumor necrosis or tumor reduction shown by CT;
and treatment >4 weeks. In our study, the total effective
rate of HIFU treatment was 72% (18/25). The overall
average survival time was 10 months, and the 1-year
survival rate was 42% (Fig. 2).
In our patients, there were no serious complications
such as pancreatic fistulae, biliary fistulae, acute
pancreatitis or blood vessel rupture. Laboratory
examination showed no adverse effects. Three patients
had first-degree skin burns after HIFU treatment, but
they recovered without any treatment.
Most patients with pancreatic cancer are considered
inoperable at diagnosis, and chemotherapy or radiation
therapy is unsatisfactory. For inoperable patients,
improving their quality of life by reducing pain and
extending survival time is critical. HIFU is a non-
invasive therapy that uses ultrasound energy from an
extracorporeal device to ablate tumors. Preclinical in vivo
studies demonstrated that HIFU safely ablates tumors or
tissues inside the body.[9, 10] However, only two studies[6,
11] have reported the effect of HIFU on unresectable
pancreatic cancer, and they only focused on treatment
safety or imaging. Our study evaluated the feasibility
of HIFU treatment for pancreatic cancer including its
clinical effect, safety, pain relief and imaging.
A study showed that about 44% of patients with
pancreatic cancer have severe pain, and persistent pain
severely affects their quality of life. Therefore, pain relief
plays an important role in pancreatic cancer treatment.
Therapies for pain relief include analgesic medications
and more invasive methods for blocking the celiac
ganglion. HIFU is a non-invasive treatment that has
analgesic effects, but the mechanism of its action is
currently unclear. Pain relief from HIFU could be
associated with damage to the innervation of the tumor
and could result from tumor coagulation necrosis.
According to our study, HIFU treatment for pain relief
is quick and effective. We hypothesize that pain relief
might occur because HIFU causes the focal temperature
to rise quickly to 70-100 ℃ and creates cavitation in the
target region. Tumor cavitation results in coagulation
necrosis, and pain fibers innervating the tumor are
damaged or undergo apoptosis.[13, 14] In our study, 44%
of the patients had a complete pain relief, and 48% had a
partial relief one week after HIFU treatment. Moreover
KPS and CA19-9 were also improved after the treatment.
These findings indicated that HIFU treatment can lead
to pain relief, which is essential to improving the quality
of life for patients with pancreatic cancer. Moreover,
5 patients with negative CA19-9 were confirmed to
have tumor necrosis by CT, and another 3 with tumor
necrosis showed a reduction in CA19-9 level by half. The
5 patients with no reduction in CA19-9 level showed
no changed echoes or tumor blood supply by B-US and
increased tumor size by CT. These data show that there
may be a relationship between necrosis and reduction of
Tumor imaging is the main factor for evaluating
HIFU treatment. Our study revealed enhanced echoes
and decreased tumor blood supply as measured by
B-US in 52% and 36% of the patients, respectively.
Tumor necrosis was confirmed in 32% of the patients
by CT. Blood flow to the tumor is usually supplied
by capillaries, indicating that HIFU can occlude
capillaries by thermal effects. Blood flow in capillaries
is slow. Thus, thermolysis is not as effective as in large
vessels. The temperature of the target region can reach
>70 ℃, causing necrosis, capillary occlusion and
fibrosis in a short time.[15, 16] We found that tumor size
was not reduced until 3 months after HIFU treatment
Fig. 2. Kaplan-Meier curve for all patients.
HIFU for unresectable pancreatic cancer
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in 2 patients. Delayed tumor shrinkage might be due
to edema or aseptic inflammation caused by HIFU
treatment. We found that HIFU can lead to a reduced
tumor size; 52% of patients had shrunken tumors or no
change in tumor size 3 months after HIFU treatment.
These data suggest that HIFU can restrain tumor growth
and that tumor ablation does occur in some cases.[17, 18]
The survival time for late-stage cancer patients is a
major concern. Currently, gemcitabine is used as the first-
line agent because of its superior survival improvement.
The reported survival time for gemcitabine-treated
patients with pancreatic cancer is 5.6 months.
Chemotherapy and radiation are second-line therapies.
However, these treatments yield poor improvement in
survival time. The difference between these studies could
be associated with different patient inclusion criteria. In
our study, the survival time was 10 months, suggesting
that HIFU treatment might be better than other
treatments in elevating the survival rate of patients.
A recent study found that a better KPS has a significant
effect on the survival of patients with pancreatic
cancer. In our study, 92% (23/25) of the patients had
an enhanced KPS after HIFU treatment. This finding
suggests that HIFU treatment might be useful in raising
the survival rate of patients with pancreatic cancer.
For a new therapeutic technique, the most important
factor is its safety. None of the laboratory tests revealed
significant changes after HIFU treatment in our study.
As to complications, 3 patients had first-degree skin
burns after HIFU treatment. However, the burns healed
without treatment within a week. We found that the
burns were due to treating the shallower areas of tumors
in the patients. To prevent complications after HIFU
treatment, we suggest that each treatment should last
<60 minutes, because longer treatment could increase
the incidence of complications. For example, longer
treatment could make the patient nervous. However,
establishment of a proper B-US pathway can reduce
the incidence of complications. We ensured that the
intestine and stomach were cleansed before HIFU
treatment because gas and fecal residue interfere with
In conclusion, HIFU treatment is effective and safe,
especially in pain relief. Moreover it increases KPS and
restricts tumor growth, while prolonging the survival
time of patients with unresectable pancreatic cancer.
The advantage of HIFU is non-invasive. A combination
of HIFU, gemcitabine or chemotherapy could result in
better therapeutic outcomes.
Acknowledgement: We are grateful to Si-Qi Wang and Xuan Luo
for their help in preparation of this article.
Contributors: ZSH proposed the study. LPZ performed research
and wrote the first draft. HW collected and analyzed the data. All
authors contributed to the design and interpretation of the study
and to further drafts. ZSH is the guarantor.
Funding: This study was supported by grants from the Ministry
of Health Research Foundation (WKJ2006-1-007) and the Hunan
Provincial National Science Foundation (11JJ5060).
Ethical approval: The study was conducted in compliance with
the protocol and approved by the Institutional Review Board and/
or Investigational Ethics Committee of Third Xiangya Hospital,
Central South University.
Competing interest: No benefits in any form have been received
or will be received from a commercial party related directly or
indirectly to the subject of this article.
1 Vulfovich M, Rocha-Lima C. Novel advances in pancreatic
cancer treatment. Expert Rev Anticancer Ther 2008;8:993-1002.
2 Michl P, Pauls S, Gress TM. Evidence-based diagnosis and
staging of pancreatic cancer. Best Pract Res Clin Gastroenterol
3 Calle EE, Rodriguez C, Walker K, Thun MJ. Overweight,
obesity, and mortality from cancer in a prospectively studied
cohort of U.S. adults. N Engl J Med 2003;348:1625-1638.
4 Dubinsky TJ, Cuevas C, Dighe MK, Kolokythas O, Hwang
JH. High-intensity focused ultrasound: current potential and
oncologic applications. AJR Am J Roentgenol 2008;190:191-
5 Vykhodtseva N, McDannold N, Martin H, Bronson RT,
Hynynen K. Apoptosis in ultrasound-produced threshold
lesions in the rabbit brain. Ultrasound Med Biol 2001;27:111-
6 Jang HJ, Lee JY, Lee DH, Kim WH, Hwang JH. Current and
Future Clinical Applications of High-Intensity Focused
Ultrasound (HIFU) for Pancreatic Cancer. Gut Liver 2010;4:
7 Hwang JH, Wang YN, Warren C, Upton MP, Starr F, Zhou
Y, et al. Preclinical in vivo evaluation of an extracorporeal
HIFU device for ablation of pancreatic tumors. Ultrasound
Med Biol 2009;35:967-975.
8 Wu F, Chen WZ, Bai J, Zou JZ, Wang ZL, Zhu H, et al. Tumor
vessel destruction resulting from high-intensity focused
ultrasound in patients with solid malignancies. Ultrasound
Med Biol 2002;28:535-542.
9 N'Djin WA, Melodelima D, Schenone F, Rivoire M, Chapelon
JY. Assisted hepatic resection using a toroidal HIFU device:
an in vivo comparative study in pig. Med Phys 2011;38:1769-
10 Jiang Z, Holyoak GR, Bartels KE, Ritchey JW, Xu G, Bunting
CF, et al. In vivo trans-rectal ultrasound-coupled optical
tomography of a transmissible venereal tumor model in the
canine pelvic canal. J Biomed Opt 2009;14:030506.
11 Sung HY, Jung SE, Cho SH, Zhou K, Han JY, Han ST, et al.
Long-term outcome of high-intensity focused ultrasound in
advanced pancreatic cancer. Pancreas 2011;40:1080-1086.
12 Brescia FJ, Portenoy RK, Ryan M, Krasnoff L, Gray G.
Pain, opioid use, and survival in hospitalized patients with
advanced cancer. J Clin Oncol 1992;10:149-155.
13 Rosenschein U, Furman V, Kerner E, Fabian I, Bernheim J,
Eshel Y. Ultrasound imaging-guided noninvasive ultrasound
Hepatobiliary & Pancreatic Diseases International Download full-text
660 • Hepatobiliary Pancreat Dis Int，Vol 11，No 6 • December 15，2012 • www.hbpdint.com
thrombolysis: preclinical results. Circulation 2000;102:238-245.
14 Sofuni A, Moriyasu F, Sano T, Yamada K, Itokawa F, Tsuchiya
T, et al. The current potential of high-intensity focused
ultrasound for pancreatic carcinoma. J Hepatobiliary Pancreat
15 Wu F, Wang ZB, Cao YD, Xu ZL, Zhou Q, Zhu H, et al. Heat
fixation of cancer cells ablated with high-intensity-focused
ultrasound in patients with breast cancer. Am J Surg 2006;
16 Wu F, Wang ZB, Zhu H, Chen WZ, Zou JZ, Bai J, et al.
Feasibility of US-guided high-intensity focused ultrasound
treatment in patients with advanced pancreatic cancer: initial
experience. Radiology 2005;236:1034-1040.
17 Li CX, Xu GL, Jiang ZY, Li JJ, Luo GY, Shan HB, et al.
Analysis of clinical effect of high-intensity focused ultrasound
on liver cancer. World J Gastroenterol 2004;10:2201-2204.
18 Xiong LL, Hwang JH, Huang XB, Yao SS, He CJ, Ge XH, et
al. Early clinical experience using high intensity focused
ultrasound for palliation of inoperable pancreatic cancer. JOP
19 Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg
ML, Modiano MR, et al. Improvements in survival and clinical
benefit with gemcitabine as first-line therapy for patients with
advanced pancreas cancer: a randomized trial. J Clin Oncol
20 Wang K, Chen Z, Meng Z, Lin J, Zhou Z, Wang P, et al.
Analgesic effect of high intensity focused ultrasound therapy
for unresectable pancreatic cancer. Int J Hyperthermia 2011;
21 Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta
E, Schüller J, et al. Gemcitabine plus capecitabine compared
with gemcitabine alone in advanced pancreatic cancer: a
randomized, multicenter, phase III trial of the Swiss Group
for Clinical Cancer Research and the Central European
Cooperative Oncology Group. J Clin Oncol 2007;25:2212-2217.
Received December 7, 2011
Accepted after revision March 28, 2012
He who walks with the wise grows wise, but a companion of fools suffers harm.
—Old Testament: Proverbs