 Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 4, 2010, pp. 414-420 |
Journal of
Cancer Research and Therapeutics, Vol. 6, No. 4, October-December, 2010, pp.
414-420
Review Article
High intensity
focused ultrasound ablation: A new therapeutic option for solid tumors
Franco Orsi1,
Paolo Arnone1, Wenzhi Chen2, Lian Zhang2
1Interventional Radiology Unit,
Division of Senology, European Institute of Oncology, 435 Via Ripamonti, 20141
Milan, Italy
2Clinical Center for Tumor Therapy of 2nd Hospital of Chongqing University of Medical Sciences, Chongqing 400010, China
2Clinical Center for Tumor Therapy of 2nd Hospital of Chongqing University of Medical Sciences, Chongqing 400010, China
Correspondence
Address: Lian Zhang, Clinical
Center for Tumor Therapy of 2nd Hospital of Chongqing University of Medical
Sciences, Chongqing 400010, China, zhangl@haifu.com.cn
Code Number:
cr10109
PMID: 21358073
DOI:
10.4103/0973-1482.77064
Abstract
Surgery has
been the standard of care in selected cases with solid tumors. However, a
majority of patients are unable to undergo surgical resection because of the
tumor sites, advanced stages, or poor general condition. High intensity focused
ultrasound (HIFU) is a novel non-invasive technique that is capable of
producing coagulative necrosis at a precise focal point within the body,
without harming overlying and adjacent structures even within the path of the
beam. Diagnostic ultrasound was the first imaging modality used for guiding
HIFU ablation in the 1990s. Over the last decade, thousands of patients with
uterine fibroids, liver cancer, breast cancer, pancreatic cancer, bone tumors,
renal cancer have been treated with ultrasound imaging-guided HIFU (USgHIFU)
worldwide. This USgHIFU system [Chongqing Haifu (HIFU) Tech Co., Ltd.,
Chongqing, China] was first equipped in Asia, now in Europe. Several research
groups have demonstrated that HIFU is safe and effective in treating human
solid tumors. In 2004, the magnetic resonance guided focused ultrasound surgery
(MRgFUS) was approved by the United States Food and Drug Administration (FDA)
for clinical treatments of uterine fibroids. We conclude that HIFU offers
patients another choice when no other treatment available or when patients
refused surgical operation. This technique may play a key role in future
clinical practice.
Keywords: High intensity focused ultrasound,
cancer, treatment
Introduction
Surgery has
been the standard of care in selected patients with solid tumors, offering the
chance of complete cure by tumor removal. However, a majority of patients are
unable to undergo surgical resection because of the tumor sites, advanced stage
of tumors, or poor general condition. Clinicians have been trying to find out
novel treatment techniques, such as radiofrequency ablation (RFA), percutaneous
ethanol injection (PEI), cryoablation, microwave coagulation, laser-induced
interstitial thermotherapy, and HIFU, to treat those patients. Among these
techniques, HIFU is the only non-invasive technique. HIFU ablation is also
known as focused ultrasound ablation, focused ultrasound surgery (FUS). The
possibility that focused ultrasound ablation might be developed as a result of
controlling local heating phenomena was introduced by Lynn et al. in the
1940s, but the technique was not
developed at that time because of inadequate targeting methods. In the 1980s,
HIFU has received considerable attention. Chongqing group began HIFU project in
China in 1988. After 10 years of basic research, Wang et al. proposed a
new conception of the ′biological focal field′ in 1997. In the last decade,
several clinical HIFU projects have been conducted by various research groups
and significant results indicated that HIFU ablation would be safe, effective,
and feasible in clinical application.
MRgHIFU or
MRgFUS
For guiding and
monitoring HIFU ablation, MRI offers excellent anatomic resolution and
temperature sensitivity for real-time treatment monitoring. Early work by Huber and Hynynen confirmed the
feasibility of MR guided focused ultrasound treatment in the breast. Huber et
al. treated one patient with HIFU followed by lumpectomy five days later.
MR imaging following treatment and histological examination following excision
revealed lethal and sub lethal damage to the tumor. Hynynen et al. then treated 11 fibroadenomas in nine
patients under local anesthesia using MR guided ultrasound. Fibroadenomas were
confirmed by biopsy pre-treatment and the effects of the treatment were
evaluated by contrast MR imaging pre- and post-treatment at 2 days, 10 days and
6 months follow-up. Contrast agent uptake was reduced or eliminated in 8 of the
11 lesions after HIFU treatment, which indicates tissue devascularization and
necrosis. The treated fibroadenomas were softer and MR imaging showed the mean
volume was smaller at six after HIFU ablation.
The feasibility
and effectiveness of MRgFUS are being tested in several other clinical
applications, which include the ablation of benign and malignant tumors and
palliative therapy of bone pain due to metastasis. However, up until now, the main indication
for MRgHIFU or MRgFUS is uterine fibroids.
Stewart et
al. and Tempany et al. have shown that MRgFUS for uterine
fibroids is feasible and safe. Although the ablation volume is only around 30%
of the targeted fibroids, patients reported either significant or partial
improvement in symptoms. Treated fibroids decreased in volume by 12% and 15% at
one and six months, respectively. The long-term follow-up also demonstrated
that patients undergoing MRgFUS for smaller fibroid volume ablation have
sustained symptom relief. However, based on the mean non-perfused volume (NPV)
ratio immediately after treatment, subjects with higher NPV ratio have
significantly greater improvement, with higher probability of intervention-free
survival. Therefore, ablating a large fraction of the volume of uterine
fibroids may be important for long-term success.
In earlier
studies, a clear pathway from the anterior abdominal wall to the fibroid
without passing through the bladder or the bowel was required; many patients
were excluded from MRgFUS because of bowel presence in acoustic pathway.
Recently, Zhang et al. have demonstrated that after the bowel
was compressed with a degassed water balloon, MR imaging-guided high intensity
focused ultrasound treatment is safe and feasible in ablating uterine fibroids
in patients whose bowel lies anterior to uterus .
USgHIFU
For guiding and
monitoring HIFU ablation, ultrasound (US) has its own advantages over other
imaging modalities. First, MRI could offer excellent anatomic resolution.
However, it has no ability to offer real-time anatomic background imaging for
temperature mapping. In contrast, ultrasound provides clear real-time
monitoring anatomic imaging without making noise or emitting ionizing particles
and radiation. Second, MRI is the only currently available technique with
proven capabilities to create quantitative temperature maps. However, it will
be very difficult to monitor the temperature changes of the tissue when the
movement occurs during HIFU, this may limit application of HIFU technology. In
contrast, ultrasound has not this limitation, and many studies have demonstrated
that US grey-scale change is reliable for monitoring the response to HIFU
treatment.Third, since the bore size of MRI is relatively small, it is
difficult to position patient, for example, when tumor locates at right lobe of
the liver. There is no such limit for USgHIFU. Therefore, USgHIFU has a
relatively wide application area.
Bone
There has been
a general consensus that US energy cannot enter bone at sufficient intensity
for therapeutic ablation because of ultrasound energy attenuation by bone.
However, it has been demonstrated that thermal lesions can be achieved even
transcranially in animals using focused ultrasound: where the tumor results in
partial or complete cortical destruction, HIFU can penetrate into the medullary
space and achieve complete necrosis.
Chen et al. first treated five patients with osteosarcoma
who were not candidates for limb salvage surgery in a pilot study. After HIFU
ablation, blood supply to the tumor was reduced and 99m Tc-MDP bone
scan demonstrated reduction in osteogenesis in the treated area. All patients
experienced reduction or elimination of pain related to the tumor and an
improvement to the range of motion of afflicted joints. Histopathology
confirmed that the treatment had reached the target area. Complete necrosis was
achieved in 103 of 120 samples.
Following this
early success, Chen et al. continued treatment in another 30
patients who had refused surgery. Complete regression was achieved in 10
patients with partial regression achieved in another 13 patients.
Recently, Chen et
al. evaluated long-term follow-up results of USgHIFU ablation
for patients with primary bone malignancies. From December 1997 to November
2004, 80 patients with primary bone malignancy were treated with USgHIFU,
including 60 in Stage IIb and 20 in Stage III (Enneking staging). HIFU combined
with chemotherapy was performed in 62 patients with osteosarcoma, 1 with
periosteal osteosarcoma and 3 with Ewing′s sarcoma. The remaining 14 patients
with chondrosarcoma, malignant giant cell tumor of bone, sarcoma of the
periosteum or unknown histology, received HIFU alone. Magnetic resonance (MR)
imaging or computed tomography (CT), and single photon emission CT (SPECT) were
used to assess tumor response. Follow-up images demonstrated completely ablated
malignant bone tumors in 69 patients and greater than 50% tumor ablation in the
remaining 11 patients. Overall survival rates at 1, 2, 3, 4, and 5 years were
89.8%, 72.3%, 60.5%, 50.5%, and 50.5%, respectively. Survival rates at 1, 2, 3,
4, and 5 years were 93.3%, 82.4%, 75.0%, 63.7%, and 63.7%, respectively, in the
patients with stage IIb cancer and 79.2%, 42.2%, 21.1%, 15.8%, and 15.8%, respectively,
in those with stage III disease. Among the patients with stage IIb disease,
long-term survival rates were substantially improved in the 30 patients who
received the full treatment-that is, complete high-intensity focused ultrasound
and full cycles of chemotherapy-compared with the survival rates for the 24
patients who did not finish the chemotherapy cycles and the six patients who
underwent partial ablation only. Only five (7%) of the 69 patients who
underwent complete ablation had local cancer recurrence during the follow-up
period.
The most
frequently observed complication was mild skin burn, usually resolving by
one-two weeks after HIFU, even without any medication. At the beginning of this
study in 1997, skin burn was mainly due to lack of experience in performing
HIFU as most occurred during the years of 1997-1999. Another observed
complication was nerve injury, it occurred in 10 of 80 patients. The following
factors may be pertinent to nerve injury: (1) Nerves can not be visualized by
ultrasound imaging, and are thus difficult to avoid in the beam path if the
anatomical location of nerves has changed; (2). Nerves are sensitive to
ultrasonic energy; and (3) Tumors were often adjacent to nerves. Bone fracture,
ligamentous laxity, epiphysiolysis, and secondary infection were also observed;
however, all of these patients recovered after surgical intervention.
Certainly,
USgHIFU therapeutic ablation of malignant bone tumors is feasible and
effective, and may eventually become part of a regimen of limb-sparing
techniques in patients with malignant bone tumors. The patients with bone
metastases could also benefit from USgHIFU and have better quality of life.
Liver
The liver has
been a target for HIFU since the early days of animal experimentation. In the
past ten years, several groups started to use USgHIFU to treat liver cancer. In
2001, Wu et al. has reported the pathological changes of hepatocellular
carcinoma (HCC) after extracorporeal ablation with high-intensity focused
ultrasound (HIFU).
From November
1998 to May 2000, 50 consecutive patients with stage IVa HCC were enrolled in a
clinical study to evaluate the response to USgHIFU ablation combined with
transcatheter arterial chemoembolization (TACE). These patients were divided
into two groups: TACE alone was performed in group 1 (n = 26), and HIFU
combined with TACE was performed in group 2 (n = 24). Tumors ranged from
4 to 14 cm in diameter (mean, 10.5 cm). Follow-up images showed absence or
reduction of blood supply in the lesions after focused ultrasound ablation when
compared with those after TACE alone. The median survival time was 11.3 months
in group 2 and 4.0 months in group 1 (P =0.004). The one-year survival
rate was 42.9% and 0% in group 1 and group 2, respectively (P <
0.01).
In Oxford, UK,
a total of 22 patients with liver metastases were treated with USgHIFU. Using
either radiological images such as MRI and contrast ultrasound, or histological
examinations, 20 of 22 patients were assessed. The results revealed that the
adverse event profile was favorable when compared to open or minimally invasive
techniques.
Recently, Zhang
et al. reported that HIFU can achieve complete tumor necrosis
even when the lesion is located adjacent to the major hepatic blood vessels.
Indeed, there is no discernible damage to the major vessels, even though the
adjacent tumor has been completely ablated.
From November
2007 to April 2009, Orsi et al. treated 17 patients with 24 liver
metastases at difficult locations.
We conclude
that USgHIFU ablation can be considered as a safe and feasible approach for
treating liver tumors at difficult locations.
Pancreas
At present,
surgery provides the best results for patients with pancreatic cancer. However,
most of the patients are not suitable for surgery when the diagnosis is made.
For patients who can not undergo surgical operation, HIFU may extend the life
expectancy and improve the quality of life.
Between
December 2000 and September 2002,
Chongqing group conducted a prospective trial on eight patients with
advanced pancreatic cancer. Patients were enrolled if they were considered
unsuitable for surgical operation and had constant localized pain. Three
patients had stage III and five patients had stage IV disease. They performed
one session of HIFU treatment in six patients and two sessions of treatment in
two patients either under general or epidural anesthesia. The pain associated
with the pancreatic lesion relieved in all patients during the follow up
period. Reduction of tumor volume was observed in all patients, ranging from
20% to 70%. The median survival time was 11.25 months. Serum amylase and
bilirubin remained at normal levels and no complications were reported.
More recently,
Orsi et al. treated seven
patients with USgHIFU between November 2007 and June 2009. All of the seven
patients were almost completely palliated in symptoms by 24 h after treatment.
The median survival time was 11 months. MDCT or MRI at 24 h after treatment did
not detect any injury of the surrounding structures. PET-CT at one month after
HIFU showed good response to HIFU .
We conclude
that HIFU is an alternative treatment option for patients with pancreatic
cancer.
Breast
Breast cancer
is the most common cancer in women and a leading cause of mortality. In the
recent years, the progressive reduction of local treatment, that achieve the
same result as standard treatment but with less morbidity and better quality of
life, has opened up new horizons toward minimally invasive technology.
In this
scenario, we believe that HIFU should be investigated deeply, as a non-invasive
new treatment option for highly selected patients suffering from early breast
cancer.
The first
randomized controlled clinical trial was conducted by the group in Chongqing.
In this study, patients were treated with either modified radical mastectomy (n=25)
or HIFU followed by modified radical mastectomy within one-two weeks (n=23).
The HIFU procedure was performed under general anesthesia in 19 patients and
under conscious sedation in four patients. The HIFU-treated area included the
tumor and 1.5-2.0 cm of surrounding normal tissue. Pathological results showed
that coagulative necrosis occurred in the cancerous tissue and the safety
margin. They also noted that the expression of PCNA, CD44v6 and MMP-9 was
significantly higher in the untreated cancerous tissue than that in the
untreated normal breast tissue. However, there was no expression in the
HIFU-treated area. Additional histological analysis using NADH staining
confirmed complete necrosis.
Wu et al. evaluated the long-term clinical results of
HIFU in another study. They treated twenty two patients with biopsy-confirmed
breast cancer. These patients were enrolled if they were deemed unsuitable for
surgery (n=6) or refused surgical resection (n=16). Among them,
four patients at stage ‡T, nine patients at stage ‡UA, eight at stage ‡VB and
one at stage ‡W. All patients received six cycles of adjuvant chemotherapy and
radiotherapy after HIFU ablation. On completion of the chemotherapy, two years
hormone therapy (tamoxifen) followed.
The absence of
blood flow was reported in 19 of 22 patients after HIFU treatment. Tumor shrank
in 14 patients and disappeared in eight patients. As anticipated, all patients
experienced a palpable breast lump following HIFU which extended to the whole
treatment area (tumor and margin) and was therefore greater than the original
tumor. Although patients were advised of this in advance, it did give rise to
anxiety, and 2 of the 21 patients elected to have mastectomy as a result. Local
recurrence occurred in two patients at 18 and 22 months after HIFU ablation.
Five years disease-free survival and recurrence-free survival were reported as
95% and 85%, respectively. It demonstrated that HIFU is a safe and effective
treatment for patients with breast cancer.
Currently,
another clinical trial is underway at the European Institute of Oncology
(Milan, Italy). Twelve patients with small breast cancers (<1.5 cm) have
been treated with USgHIFU in a single session. After HIFU, all the patients
underwent conservative surgery in order to obtain the standard breast cancer
surgical treatment and an accurate histo-pathological assessment to confirm the
correct HIFU treatment. The pathologic results have shown that the tumors have
been ablated without side effects.
Kidney
Renal cancer
may also be treated with this non-invasive approach. Wu et al. described
a series of 13 patients with renal cell carcinoma. All the 13 patients received
HIFU treatment safely, including 10 who had partial ablation and three who had
complete tumor ablation. After HIFU, hematuria disappeared in seven of eight
patients and flank pain of presumed malignant origin disappeared in 9 of 10
patients. No side effects occurred after ablation using an experimental
handheld device. Further investigations continue to study the efficacy of HIFU
treatment of renal cell carcinoma for both cure and palliation.
Illing et
al. treated eight patients with renal cancer in Oxford. After a single
therapeutic HIFU session under general anesthesia, the results were evaluated
with either radiological images such as MRI or contrast ultrasound, or
histological examinations. The results revealed that the adverse event profile
was favorable when compared to open or minimally invasive techniques.
A number of
other patients in Oxford have been treated outside any trials. A patient with a
5 cm biopsy proven renal cell carcinoma in a transplant kidney was treated
twice with 90% ablation of the tumor (confirmed histologically after a
subsequent partial nephrectomy). A transplant kidney would seem to be ideally
suited to HIFU treatment as it is sited in the groin area and thus ribs do not
pose a problem. Furthermore, perinephric fat, which on occasions seems to
impair treatment, has been removed.
Uterus
In China, Wang et
al. have reported their preliminary results of HIFU treatment for
symptomatic uterine fibroids in 2002. Between July 2001 and January 2003, He et
al. treated 23 patients with HIFU at
one center. Patients were enrolled if they refused hysterectomy. The fibroids
were between 4 and 8 cm in diameter and located at the anterior wall of uterus.
The average volume of menstruation and uterine volume decreased throughout the
follow-up period and the average size of uterine fibroids reduced in 17
patients with a mean reduction of 78.9%. The fibroid in one patient was
resected because of the persistent menorrhagia. Histopathological results from
this patient showed that normal tissues around the treated area were undamaged.
Unfortunately, four patients had temporary numbness on the lower limbs because
of damage to the sciatic nerve which is now avoided by changing the treatment
protocol.
In 2004, Wu et
al. reported the use of HIFU in treatment of 85 patients between 1997 and
2001 with uterine fibroids at centers in China. Over the last three years, this
JC model HIFU system has been modified and thus led to a very low level of
adverse effects. Currently, this technique has been clinically considered as an
alternative treatment for patients with uterine fibroids in China.
In Spain, a
total of 54 patients with uterine fibroids less than 13 cm in diameter were
treated in Hospital Mutua de Terrassa (HUMT) from January to Dec 2009. The
post-operative pain score was 0 (at 4 h after HIFU) and all patients returned
to their normal life within 24 to 48 h after the treatment. The treated volume
covered more than 80% of the fibroid in most cases. The data showed a
significant improvement in uterine fibroid symptom and quality of life
(UFS-QOL) scores. In the Medical Center of Central Bank, Moscow, Russian ,
Khitrova treated 61 patients with 143 fibroids (1-7 lesions per patient), there
was no complication after treatment, only two patients with submucous fibroids
had two-day temperature elevation (under 38.5°C). No skin burns or nerve injury
occurred. All clinic signs later disappeared, and two pregnancies subsequently
occurred in two patients.
Others
HIFU has been
successfully used in China for the treatment of soft tissue sarcoma. It has been used as an organ preserving
treatment in patients with uterine adenomyosis. Wang et al also reported that
US-guided HIFU ablation appears to be safe and effective for the treatment of
abdominal wall endometriosis. The cyclic pain disappeared in all patients
during a mean follow-up of 18.7 months.
Conclusions
These results
from different groups are encouraging. HIFU ablation can achieve complete
response without significant adverse effects; therefore, it is a safe,
effective and feasible modality for the destruction of benign and malignant
solid tumors. On the basis of the results from clinical trials and studies, we
conclude that HIFU seems to be a new therapeutic option for solid tumors.
Acknowledgement
We are grateful to
Wendy (Wenyi) Zhang for helping us to edit and revise this review.
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