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Οriginal Paper
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CLINICAL PRACTICE
High Intensity Focused Ultrasound
Treatment for Patients with Local
Advanced Pancreatic Cancer
Hui-feng Gao, Kun Wang, Zhi-qiang Meng, Zhen Chen, Jun-hua Lin,
Zhen-hua Zhou, Peng Wang, Wei-dong Shi and Ye-hua Sheng
Department of Integrated Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Key Words:
High intensity focused ultrasound;
Local advanced
pancreatic cancer;
Palliative care.
Corresponding author: Kun Wang, Ph.D., Department of Integrated Oncology, Fudan University Shanghai Cancer Centre;
Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China;
Tel.: +86-21- 6417-5590, Fax: +86-21- 6443 -7657; E-mail: [email protected]
ABSTRACT
Background/Aims: To evaluate the safety and
efficacy of high intensity focused ultrasound (HIFU)
therapy in patients with local advanced pancreatic
cancer. Methodology: 39 patients with local advanced
pancreatic cancer were treated with HIFU, including
26 male and 13 female patients. The locations of
the tumours were as follows: head of pancreas in 7
patients, body and/or tail of pancreas in 32 patients.
Pain relief, time to progression (TTP), median survival
and complications were analysed after HIFU treatment.
Results: There were no severe complications or
INTRODUCTION
Pancreatic cancer is a highly lethal disease
worldwide. A total of 45,220 new pancreatic cancer
cases and 38,460 pancreatic cancer deaths are
estimated to occur in the United States in 2013 (1). In
China, the incidence of pancreatic cancer is increasing
by approximately 1,746 estimated new cases in
Shanghai in 2005 for both sexes. It has become the
fifth cause of the cancer death of cancer disease (2).
Due to the poor prognosis, the mortality is almost
100% (3). Surgical resection gives the best chance for
a possible cure. As typical symptoms are imperceptible
in the early stage, 85%-90% of newly diagnosed
pancreatic tumors are considered unresectable due to
local advanced disease or presence of metastasis (4).
High intensity focused ultrasound (HIFU) has been
successfully used as a novel hyperthermia therapy of
tumors in clinical application. HIFU is able to lead a
potential coagulative necrosis in-depth tissue without
damaging peripheral vital anatomy structures. HIFU
application in the palliative treatment of pancreatic
cancer could be useful in patients with symptoms
that would benefit from local tumor restriction. The
first report (5) of HIFU treatment case in pancreatic
cancer used Model FEP-BY01 machine. HIFU is now
applied for pancreatic cancer treatment in China. This
article reports clinical experience of pancreatic cancer
with the extracorporeal Model JC HIFU therapy device
(Chongqing Haifu Tech, Chongqing, China) at a single
institution. The principal objective of this study was
to prospectively evaluate the safety and efficacy of
HIFU in patients with local advanced pancreatic cancer.
METHODOLOGY
Eligibility criteria
Eligible patients
with
histologically
Hepato-Gastroenterology 2013; 60:00-00 doi 10.5754/hge 13498
© H.G.E. Update Medical Publishing S.A., Athens
and/or
adverse events related to HIFU therapy in any of the
patients treated. Pain relief was achieved in 79.5% of
patients. Median TTP was 5.0 months. The median
overall survival time was 11 months. 6-month and
1-year survival rate for patients were 82.1% and
30.8% respectively. Conclusions: Although this study
may have limitations, preliminary results demonstrate
the safety of clinical application of HIFU for pancreatic
cancer and reveal it to be a promising mode of
treatment for local advanced pancreatic cancers.
cytologically proven locally advanced pancreatic
carcinoma were enrolled for study. In addition, the
patient should have constant cancer-related pain of
visceral origin localized to the region of the middle
and upper back. A Karnofsky performance scale (KPS)
score of ≥60% was required. In addition, adequate bone
marrow (white blood cell count >2,500 /mL, platelet
count >80,000 /mL, hemoglobin >8 g/mL), kidney
(serum creatinine concentration <1.5 mg/dL, blood urea
nitrogen <20 mg%) and liver (serum transaminase level
<2 times the upper normal range) function was required;
an exception was made for hyperbilirubinemia due to
obstructive jaundice. Patients were also excluded if their
lesion was undetectable by ultrasound or if the patients
had a serious or uncontrolled concurrent medical illness.
Treatment methods
The patients who refused chemotherapy, or had a
previous history of failure treatment of chemotherapy
and/or radiotherapy, received only HIFU therapy.
Others received combined therapy. These patients
received gemcitabine 1,000 mg/m2 intravenously over
30 min on days 1, 8, and 15, and concurrent HIFU
therapy in the first week. The treatment was given
every 28 days and continued until disease progression,
patient refusal, or an unacceptable toxicity. HIFU
treatment times were decided by two experienced
HIFU doctor after assessment of follow-up CT or MRI.
Equipment
The machine (Model JC) is provided by Chongqing
Haifu Tech, Chongqing, China. It has many functions
including real-time ultrasound (US) localization
and monitoring for tumor lesion, three-dimensional
targeted scanning, calculating treatment volume in
targeted areas, and feedback control of treatment dose.
HIFU Treatment for Patients with LAPC
Hepato-Gastroenterology 60 (2013)
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The therapeutic parameters and methods of HIFU
treatment
Pre-operation preparation
Before treatment, fasting, cathartic, skin cleaning
in treatment area should be conducted for patients.
Anesthesia method and treatment parameters of
patients
Sedation and analgesia anesthesia method is
conducted for patients. The parameters of therapeutic
ultrasound transducer are the followings: 1) frequency
0.85 MHz; 2) focal length 135.0 mm; 3) diameter
20 cm; 4) scanning methods: fixed-point method.
Treatment methods
The patient was placed prone and carefully
positioned, so that the skin overlaying the lesion to
be treated was in contact with degassed water. Realtime US was used to target the tumor by moving the
integrated probe, and the tumor was divided into
slices with 5mm separation using US images. By
scanning the HIFU beam in successive sweeps from
the deep to the shallow regions of the tumor, the
targeted regions on each slice were completely ablated.
Evaluation of efficacy and side effects
After HIFU treatment, complete blood count with
differentials, serum chemistry and urinalysis and Serum
CA19-9 levels were measured. Treatment-related
toxicities were assessed using the National Cancer
Institute Common Toxicity Criteria version 2.0. Pain
intensity was assessed for each patient using a numerical
rating scale (NRS) from 0 to 10 (0 = ‘no pain at all’, 1–3 =
‘mild pain’, 4–6 = ‘moderate pain’, 7–9 = ‘severe pain’, 10 =
‘unbearable pain’) before and 1 week after HIFU. Tumor
response was evaluated by CT or MRI scan 1 month after
HIFU treatment. A complete response (CR) was defined
as a total resolution of all evidence of primary tumor. A
partial response (PR) required a 50% reduction in the
maximum perpendicular tumor measurements. Stable
disease (SD) was defined as less than 50% reduction
and less than 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.
Statistical methods
Statistical calculations were performed using
SPSS software (version 13.0). This study conducts
Log-rank test for differences testing and Spearman
rank correlation analysis for HIFU dosimetric
analysis. Statistical results are reported as p values.
RESULTS
Patient characteristics
There are altogether 39 cases of local advanced
pancreatic cancer patients in this study, 26 cases of
which are male and 13 of which are female. The ages
of these patients are between 42 years to 79 years
(median age 58 years). All the patients accepted in
this study are not suitable for surgery, 7 patients
have pancreatic head cancers and 32 patients have
pancreatic body or tail cancers. Besides, 35 cases
have the indicator Ca19-9 level increased (>37 U/mL).
14 patients received only HIFU therapy (10 patients
had a previous history of failure treatment with
chemotherapy and/or radiotherapy. Four other patients
were not felt to be suitable candidates for chemotherapy
and/or radiotherapy with KPS = 60). 25 patients
received combined therapy; 33 patients in the study
received only once of HIFU therapy, 4 patients received
twice HIFU therapy and others more than two times.
FIGURE 1 (ABOVE) & 2 (BELOW) Comparing the scans pretreatment and 1 month after
HIFU treatment, CT/MRI were reviewed with regard to changes in coagulation necrosis
performance on target tumor. Contrast enhanced CT or MRI showed decrease or disappear of blood supply in target region and circular enhancement in tumor periphery
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Hepato-Gastroenterology 60 (2013)
Gao HF, Wang K, Meng ZQ, et.al.
Long-term prognosis after HIFU
The median overall survival time was 11.0 months
and median TTP was 5.0 months. 6-month and 1-year
survival rate for patients were 82.1% and 39.5%
respectively. For patients who were treated by HIFU single,
the median survival was 8 months and 1-year survival
rate were 14.3%. For patients who were treated by both
HIFU and chemotherapy, the median survival was 12.0
months and 1-year survival rate were 49.9% (Figure 3).
The survival time was significantly different (p <0.01)
between the HIFU group and combined therapy group.
But, the TTP was no significantly different (p >0.01)
between the HIFU group and combined therapy group.
FIGURE 3.For patients who were treated by both HIFU and chemotherapy, the median
survival was 12.0 months and 1-year survival rate were 49.9%
Treatment-related toxicities
There were 3 patients (7.7%) with increase of
serum amylase and recovered within one week.
There were 2 patient (5.1%) with gastrointestinal
dysfunction, such as bloating, poor appetite and
mild vomiting. No severe complications or adverse
events related to HIFU therapy (such as tumor
rupture or hemorrhage, gastrointestinal bleeding
and skin burn) were seen in any of patients treated.
Pain relief
All 39 patients complained of abdominal or back
pain consistent with tumor-related pain prior to HIFU
therapy. The complete remission of pain (0 pain score
and no need for opioid analgesics) was observed in 9
patients (23.1%), a partial remission of pain (decrease
in pain score by 2 or more) was observed in 22 patients
(56.4%), and no improvement of pain was seen in 8
patients (20.5%). Pain relief was observed in 79.5%
(31/39) of patients who had pain prior to HIFU therapy.
The serum CA19-9 level pretreatment and 1 month
after HIFU treatment
At entry to the study, 35 patients have the indicator
CA19-9 level increased (>37 U/mL) in 39 patients. After
one month of HIFU, compared to the pretreatment level,
the serum CA19-9 level was reduced in 19 (48.7%) of 39
patients, and it was increased in 15 (39.5%) of 35 patients.
The serum CA19-9 level was no difference compared
to the pretreatment level in 5 (12.8%) of 39 patients.
Short-term efficacy after HIFU
The response in 39 patients was evaluated by images
on target tumor treated by HIFU. Comparing the scans
pretreatment and 1 month after HIFU treatment,
CT/MRI were reviewed with regard to changes in
coagulation necrosis performance on target tumor.
Contrast enhanced CT or MRI showed decrease or
disappear of blood supply in target region and circular
enhancement in tumor periphery (Figures 1 and 2).
The necrosis area in CT/MRI after HIFU treatment were
as same as the grayscale change area monitored by realtime monitoring during the HIFU treatment. The result
showed that 5 patients (12.8%) achieved a partial
response and no patient achieved complete response, 25
patients (64.1%) and 9 patients (23.1%) had responses
of no change and progressive disease, respectively.
DISCUSSION
Local advanced pancreatic cancer remains a
challenging malignancy to treat. Approaches that use
chemotherapy, radiotherapy, or both have significant
efficacy limitations (6). As a non-invasive, non-surgical
treatment, HIFU for treatment of pancreatic cancer is
widely available in China (7,8). HIFU for the palliative
treatment of local advanced pancreatic cancer may
be useful in patients who develop symptoms that
would benefit from local tumor control (9). The
primary mechanisms of HIFU are associated with
the delivery of energy to the target tissue that causes
coagulative necrosis by thermal effects and possibly
cavitation. Different with other ablation therapies,
HIFU does not require the insertion of an applicator
into a target tissue and an extracorporeal source
can be used to treat large-volume tumors with realtime imaging guidance (7). In animal experiments
and clinical studies, it has been proven that focused
ultrasound can propagate through the abdominal
wall and ablate target tumor, thereby treating tumors
in pancreas (10). This study shows that there were
no sever complications of adverse events related to
HIFU therapy observed in any of the patients treated.
Pain is the most common and serious clinical
symptom in patients with pancreatic cancer. Resulting
from both tumor expansion and tumor invasion of
the celiac and mesenteric plexus, the pain can be both
neuropathic and inflammatory. The typical pain of local
advanced pancreatic cancer is a dull, fairly constant
pain of visceral origin localized to the region of the
middle and upper back. In the management of patients
with local pancreatic cancer, pain control is an essential
aspect. Pain management consists of a combination of
antitumor therapy, analgesic drug therapy, anesthetic
blocks, and behavioral approaches. In clinical practice,
chronic opioid narcotics have undesired side-effects
ranging from mild constipation to respiratory
depression and altered mental status. In addition, some
opioids have a dysphoric effect that can significantly
impact the patients’ quality of life (11). Early clinical
trial results show that the HIFU treatment of pancreatic
cancer has analgesic effect, although the mechanism of
action still has not been precisely identified, and may be
related to ultrasound energy destroying adjacent nerves,
even coeliac plexus, while inducing tumor coagulation
necrosis. The study reveals that 87.5%–100% of
patients received partial or entire pain relief (7,12). The
patients’ daily activities, quality of life, and psychological
status will be markedly improved after pain relief.
For decades, has been gemcitabine the most widely
used chemotherapeutic agent in local advanced
pancreatic cancer. The unique mechanism of action
and favorable toxicity profile of gemcitabine have
allowed exploration of many novel gemcitabine-based
combination regimens as treatment for pancreatic
cancer. Besides erlotinib, multiple other agents with
diverse mechanisms of action in combination with
gemcitabine have been tested in randomized clinical
HIFU Treatment for Patients with LAPC
Hepato-Gastroenterology 60 (2013)
treals, with no improvement in outcome (13). That
means, unfortunately, until now no effective modality
has been identified for the treatment of patients with
local advanced pancreatic disease. The median survival
time is 6–10 months for patients with local advanced
pancreatic cancer. In this study, comparing patients who
were treated by HIFU single with who were treated by
both HIFU and chemotherapy, median survival duration
was 8.0 months versus 12.0 months (p <0.05). The
survival rate at 12 months was 14.3% for HIFU single
patients and 49.9% for both HIFU and chemotherapy
patients. Notably, patients who were treated by both
HIFU and chemotherapy had a longer median survival
than patients who were treated by HIFU single. HIFU
is an attractive technique that might achieve local
tumor control as well as increasing permeability of
drug molecules. The possibility of synergistic effect
between HIFU and chemotherapy agent was suggested
(14,15). In patients with an ECOG performance status
of 0 or 1, concurrent chemotherapy and HIFU is a
tolerated treatment modality with promising activity.
On the other side, almost 70% of patients with
pancreatic cancer are at least 65 years old at diagnosis,
so side effect related to external radiation and antitumor
drugs may be very severe (7). In this study, the patients
who had a previous history of failure treatment with
chemotherapy and/or radiotherapy and who were not
felt to be suitable candidates for chemotherapy and/or
radiotherapy with KPS = 60, received HIFU treatment
successful. To those patients who are unable or
unwilling to receive treatment with chemotherapy and/
or radiotherapy, HIFU therapy is an available choice. It is
worth noting that 4 patients received HIFU therapy twice
and 2 patients received it more than twice. Different with
radiotherapy, HIFU therapy is not limited by dose-limiting
toxicity. That means patients with local pancreatic
cancer may benefit from HIFU treatment repeatedly.
Although this study may have limitations, we deem
that treatment of local advanced pancreatic tumors with
HIFU may result in local tumor response or a clinically
beneficial outcome by improving pain, functional status,
quality of live, and survival. A randomized controlled
study is necessary to determine our assumption.
In conclusion, HIFU is a safe and effective therapeutic
option for patients with local advanced pancreatic
cancer. This treatment may be effective for local
tumor control. This approach would be a feasible
option, both for curative and palliative purposes.
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