High-intensity focused ultrasound treatment for patients with unresectable pancreatic cancer

Changsha, China

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

Changsha, China

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 pancreatic cancer.

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)

pancreatic cancer; high-intensity focused ultrasound; therapy

Introduction

Pancreatic cancer produces the worst outcomes among all malignant tumors. Its one-year survival rate is estimated to be ＜10% and the median 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.[3]Therefore, the improvement of the quality of life must be attempted in patients with unresectable pancreatic cancer.

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.

Methods

Patients

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 pathologicallyor 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 patients.

Equipment

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.[7]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 filtered water.

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 ablateddot (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 system.

Preparation

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 liquidonly 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.

Treatment procedure

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.

Observation indices

Laboratory examinations each week after 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.

Statistical analysis

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 pairedttest. The rate of remissionand the effectiveness were determined by the Chi-square test. Survival time was evaluated using the Kaplan-Meier method. APvalue ＜0.05 was considered statistically significant.

Results

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 followup 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 t1was 183.3±14.6 msec; the mean t2was 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,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).

Table 1.Characteristics of patients before and after HIFU treatment

Table 2.Pain relief after HIFU treatment (n, %)

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.

Fig. 2.Kaplan-Meier curve for all patients.

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.

Discussion

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 noninvasive therapy that uses ultrasound energy from an extracorporeal device to ablate tumors. Preclinicalin vivostudies 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[12]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 CA19-9.

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 treatmentin 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 firstline agent because of its superior survival improvement. The reported survival time for gemcitabine-treated patients with pancreatic cancer is 5.6 months.[19]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.[20]A recent study found that a better KPS has a significant effect on the survival of patients with pancreatic cancer.[21]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 B-US imaging.

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.

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December 7, 2011

Accepted after revision March 28, 2012

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

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; Email: shaihongzhu@hotmail.com)

? 2012, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(12)60241-0