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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 831-835

High-intensity focused ultrasound ablation for advanced pancreatic cancer


1 Department of Oncology Minimally Invasive, The 307th Hospital of PLA, Beijing, China
2 Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Wuwei Yang
Department of Oncology Minimally Invasive, The 307th Hospital of PLA, No. 8 Dongdajie Street, Fengtai District, Beijing 100071
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_408_18

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 > Abstract 


Aims: The aim of this study was to evaluate the efficacy, safety, and survival factors of high-intensity focused ultrasound (HIFU) ablation in the treatment of advanced pancreatic cancer.
Subjects and Methods: A retrospective analysis was conducted between September 2010 and March 2016. Advanced pancreatic cancer patients with HIFU treatment were enrolled in the analysis to evaluate the efficacy of local ablation, pain relief, and relative complications of HIFU therapy. The main factors that affected Overall survival rate (OSR) and median survival time (MST) were also analyzed.
Results: Eighty-six patients received HIFU treatment, with a total of 93 treatments performed, and 83 cases were evaluated. Complete response rate (RR) was 3.6% (3/83) and partial RR was 79.5% (66/83). After HIFU treatment, pain reduction was observed in 74 patients, and the total remission rate was 97.6% (74/76). The total MST was 9.9 months (2–58.7 months), the total OSR in 1 and 2 years was 41.5% and 9.6%, respectively. Minor complications occurred in 97.7% (42/43) patients, including transient fever, abdominal pain, skin burn, and amylase elevation. The univariate analysis showed that the clinical stage, treatment method, ablation efficacy, and combined treatment were significant prognostic factors.
Conclusion: HIFU can significantly alleviate cancer-related pain and prolong the survival time of patients with pancreatic cancer.

Keywords: High-intensity focused ultrasound, pancreatic cancer, survival factors


How to cite this article:
Zhu B, Li J, Diao L, Ma K, Fan Y, Yang W. High-intensity focused ultrasound ablation for advanced pancreatic cancer. J Can Res Ther 2019;15:831-5

How to cite this URL:
Zhu B, Li J, Diao L, Ma K, Fan Y, Yang W. High-intensity focused ultrasound ablation for advanced pancreatic cancer. J Can Res Ther [serial online] 2019 [cited 2019 Aug 17];15:831-5. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/831/264290




 > Introduction Top


The previous research consistently shows that pancreatic cancer, which has a 98% mortality ratio, has been the fourth leading cause of cancer-related deaths in the United States and the Western world. With only 5% overall 5-year survival rate and 3−5 months of median survival time (MST), pancreatic cancer leads among all cancer types with respect to the worst outcomes.[1],[2] Although surgery is considered the only way to cure pancreatic cancer patients, >80% of patients do not have the chance for curative surgical resection because of locally advanced or metastatic disease at the time of diagnosis.[3] In addition, the effects of traditional medicine and radiotherapy are not satisfactory. Recently, noninvasive ablation therapy and interventional techniques have achieved encouraging effects on the treatment outcomes of advanced pancreatic cancer.[4],[5],[6],[7] High-intensity focused ultrasound (HIFU) therapy is a noninvasive ablation method, which uses focused ultrasound (US) energy from an extracorporeal source that conducts thermal denaturation of tissue without affecting overlying or surrounding tissues.[8] In this article, we evaluate the clinical application of the HIFU technique in the treatment of advanced pancreatic cancer in a cohort of 86 patients.


 > Subjects and Methods Top


Patients characteristics and treatment protocol

Eighty-six patients with advanced pancreatic cancer who received HIFU treatment at our hospital between September 2010 and March 2016 were enrolled in the study [Table 1].
Table 1: Patient characteristics

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The therapeutic HIFU system (Chongqing Haifu HIFU; Chongqing Haifu, Chong-qing, China) was used to treat all patients with local ablation therapy. All patients had a liquid only diet beginning 3 days before HIFU treatment and received a colon cleanse the night before treatment. The skin area for the HIFU treatment was shaved and cleaned with degassed water beforehand.

After the patients lay 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 administered the treatment controlled by a computer. The treatment plan was adjusted according to imaging changes during the HIFU procedure.

Several clinical studies suggest that the combination of HIFU with chemotherapy or radiotherapy can achieve a higher clinical benefit rate and longer survival than HIFU therapy alone. Considering a patient's general situation and willingness to be treated, we provided follow-up treatment, including intravenous chemotherapy and radiotherapy. In chemotherapy, we used combined or single-agent therapy, which is recommended by the National Comprehensive Cancer Network Guidelines, such as gemcitabine, capecitabine, and oxaliplatin.

HIFU ablation followed by radiotherapy is also a promising treatment method. HIFU should be carried out after or simultaneously with radiotherapy. For some patients, we used three-dimensional conformal radiation therapy, and for patients who repeated HIFU treatment, the curative effect of the first HIFU treatment was evaluated.

Evaluation criteria

Follow-up imaging examination, including magnetic resonance imaging (MRI) or enhanced computerized tomography scan, was performed 1 month after HIFU ablation, and the effect of local ablation on the pancreatic lesion was evaluated with reference to the Modified Response Evaluation Criteria in Solid Tumors. The classification assessment was conducted as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The efficacy of local ablation was calculated on the basis of CR + PR. HIFU is an effective therapy for palliation of pancreatic cancer-related pain. According to the World Health Organization pain relief evaluation criteria, we applied numerical rating scales (NRS) to assess changes in pancreatic cancer-related pain 3 days after HIFU ablation.

On the basis of the classification criteria recommended by the society of intervention radiology (SIR), we assessed the incidence and severity of various complications. We followed up with all patients from the date of HIFU treatment and calculated the 1-year and 2-year overall survival rates (OSR) and MST.

We stratified major clinical factors that may be related to survival time, such as gender, clinical stage, tumor diameter, time to treatment, treatment power, type of anesthesia, operative method, local ablation effect, and combined treatment and performed univariate and multivariate analysis.

The data were analyzed using the Statistical Package for Social Sciences version 16 (SPSS 16.0 IBM, Chicago, USA) for Windows. Measurement data, which were expressed as mean and standard deviation, and numeration data were statistically analyzed by the t-test and the Chi-square test, respectively. The significance level was established at P < 0.05.

Survival time was estimated using the Kaplan–Meier method. The comparison of the survival curves was performed using the log-rank test (single factor analysis). The comparison of survival factors was performed using the Cox proportional risk regression model. Variables with statistical significance in the single factor analysis were included in the multiple factor analysis, test level a = 0.050.


 > Results Top


Eighty-six patients were treated with HIFU ablation, with a total of 93 treatments performed, the average treatment power was 369W plus 50W (range, 210W−420W). The average time of treatment was 1291s plus 876s (range, 103s−5877s). Three patients were lost to follow-up, 83 patients were evaluated for curative effect, and complications were evaluated in 90 treatments.

Effect of local ablation

The total response rate of 83 patients was 83.1% (69/83), including CR, 3.6% (3/83); PR, 79.5% (66/83); SD, 13.3% (11/83); and PD, 3.6% (3/83). Typical cases with complete necrosis on MRI imaging are shown in [Figure 1]a and [Figure 1]b.
Figure 1: Contrastenhanced T1weighted magnetic resonance images (a) before and (b) 1 month after highintensity focused ultrasound ablation for advanced pancreatic cancer. No evidence of contrast enhancement in the treated lesion (arrowhead) illustrates complete coagulation necrosis

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Effect of pain rating reduction

Before HIFU treatment, 76 patients had cancer-related pain; the average NRS pain score was 6.20 plus 1.5 points. After HIFU treatment, pain rating reduction was observed in 74 patients, the total remission rate was 97.6% (74/76), and the average pain score was 2.2 + 1.9 points, which was significantly lower than that before operation (P < 0.001). Complete mitigation of pain was observed in three patients with severe pain and ten patients with moderate pain. Pain grading of 22 patients with moderate pain and 20 patients with severe pain was reduced to mild pain. Severe pain in 12 patients was reduced to moderate pain. Pain scores of the other four patients with moderate pain and one patient with mild pain were reduced, but the pain grading score did not change.

Survival and safety evaluation

A total of 86 cases were followed up until March 2016, and three cases were lost. The success rate of follow-up was 96.5%. The total MST was 9.9 months (2−58.7 months), and Stage III and IV MST was 14.2 months (5.0−58.7 months) and 9.4 months (2−26.7 months), respectively. The total OSR in 1 and 2 years was 41.5% and 9.6%, respectively. For Stage III and IV patients, OSR in 1 and 2 years were 60.3% and 11%, 31.7% and 9.2%, respectively [Figure 2]. Minor complications (SIR-A and B) accounted for 97.7% (42/43), however, no severe complications were observed in all enrolled patients [Table 2].
Figure 2: Overall survival of enrolled patients (P = 0.019)

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Table 2: Society of intervention radiology classification and overall incidence of complications

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Analysis of influencing factors of prognosis

Univariate analysis

A univariate analysis of all factors and MST showed that the clinical stage, treatment method, ablation efficacy, and combined treatment were significant influencing factors [Table 3]. Further subgroup analysis showed that MST in the combined treatment group reached 16.5 months in stage III patients, while MST in the combined chemotherapy plus radiotherapy group reached 23.7 months [Table 4].
Table 3: Analysis of factors associated with single factor clinical prognosis

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Table 4: Subgroup analysis of the effects of different treatments on survival

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Multivariate analysis

Influencing factors which were significant in the above univariate analysis were included in the multivariate analysis. The Cox proportional hazards regression model showed that the following factors were statistically significant, clinical stage (P = 0.028), combination therapy (P = 0.007), and ablation effect (P = 0.002).


 > Discussion Top


Although the incidence of pancreatic cancer is only 1%–2%, it is a common cancer with an occurrence rate that increases every year. Pancreatic cancer produces unsatisfactory outcomes with current therapies and has an extremely poor prognosis, due to its high malignancy and a lack of early specific diagnostic methods. In the past 30 years, the survival rate of other gastrointestinal malignant tumors has been significantly improved, but the prognosis of pancreatic cancer remains extremely poor. Previous studies suggested that the MST of untreated progressing pancreatic cancer was only 3 months. Although there are many standard options, which are recommend by guidelines such as radiotherapy and chemotherapy, they offer a very limited survival benefit in patients with untreated progressing pancreatic cancer. For patients with late-stage (TNM III or IV), the MST is only 9.2−11.7 months and 3.0−5.5 months, respectively.[3] HIFU therapy has several specific advantages, such as reduced healthy tissue damage, effective reduction of tumor load, rapid relief of pain and other symptoms, and the possibility of prolonging survival benefit. Rapid development and breakthroughs in HIFU therapy in terms of clinical application to various solid tumors has also been achieved. Due to its noninvasive technology, HIFU may play a significant role in treating pancreatic cancer patients.[9]

The feasibility of high-intensity focused ultrasound in the treatment of advanced pancreatic cancer

For the treatment of patients with advanced pancreatic cancer, HIFU has several advantages such as being noninvasive, repeatable, less pain, and short recovery time. By damaging the nerve fibers which innervate the tumor, HIFU treatment can effectively alleviate cancer-related pain without any significant complications.[10],[11],[12] Through our study, data analysis some preliminary conclusions can be summarized as follows:First, HIFU treatment can effectively achieve local ablation. The total ablation effect was 83.1% (CR and PR). Although HIFU therapy reflects most advantages of the ablation technique, ultrasonic energy is easily disturbed and reduced by other factors on the treatment channel. Therefore, HIFU therapy may have some uncertainties in the efficacy of ablation, but with the continuous development of the HIFU technique and the accumulation of clinical practice, HIFU therapy for pancreatic cancer has been able to achieve a stable and satisfactory ablation effect. Second, HIFU therapy can effectively alleviate cancer-related pain. HIFU can be used to destroy the celiac plexus, which is attached to the intraperitoneal vessels of the abdominal cavity, to effectively relieve cancer-related pain and allow treatment to be repeated. Similar to the results of related studies,[11] the rate of remission in our study was 97.6%. Moreover, nerve metastasis is an important metastatic pathway of pancreatic cancer; therefore, it is also valuable to evaluate whether the damage of the celiac plexus can prolong the control time of the tumor.

HIFU therapy incorporated with B-mode ultrasonography to monitor the therapeutic procedure has widely recognized safety and efficacy in treating pancreatic cancer without laparotomy and puncturation as there are no serious associated complications such as bleeding, infection, perforation, and pancreatic fistula.[13],[14] In our study, only one patient had elevated serum amylase after treatment, but the patient had no symptoms of pancreatitis and recovered to normal levels within 1 week after symptomatic treatment. No serious complications were found in our study. In conclusion, to ensure the safety of HIFU therapy, clinicians should strictly follow the treatment plan and monitor the response to treatment.

The relative factors which affect the prognosis of HIFU therapy in pancreatic cancer were preliminarily discussed in our study, and the effect of ablation therapy was further confirmed. Currently, due to the nonstandard application of HIFU therapy, a considerable amount of HIFU treatments are only used in cases of hyperthermia and sensitization. Therefore, studying the ablation effect of HIFU should be an important goal for the treatment of tumors. The effective application of this technique in the treatment of pancreatic cancer can only be achieved if the effect of ablation can be confirmed. Several studies have reported that stage III pancreatic cancer patients can achieve an MST of 34 months by radiofrequency ablation combined with interventional therapy and radiotherapy.[15] Consequently, reasonable application of HIFU therapy and implementation of comprehensive treatment strategies can result in better therapeutic outcomes.


 > Conclusion Top


Our study preliminarily indicates that HIFU therapy is feasible and relatively safe. Used alone or in combination with systemic chemotherapy, HIFU therapy can effectively alleviate cancer-related pain and offer an additional survival benefit with few serious complications. Because of the limitation of our study such as that from being a single-center research and having a small number of cases, multicenter randomized clinical trials to evaluate the long-term efficacy and to determine the future role of HIFU therapy for the treatment of advanced pancreatic cancer will be required.

Financial support and sponsorship

This study was supported by the Capital Clinical Fund Program of China (Z151100004015192).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Marinova M, Rauch M, Mücke M, Rolke R, Gonzalez-Carmona MA, Henseler J, et al. High-intensity focused ultrasound (HIFU) for pancreatic carcinoma: Evaluation of feasibility, reduction of tumour volume and pain intensity. Eur Radiol 2016;26:4047-56.  Back to cited text no. 11
    
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Li CC, Wang YQ, Li YP, Li XL. High-intensity focused ultrasound for treatment of pancreatic cancer: A systematic review. J Evid Based Med 2014;7:270-81.  Back to cited text no. 13
    
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Rombouts SJ, Vogel JA, van Santvoort HC, van Lienden KP, van Hillegersberg R, Busch OR, et al. Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg 2015;102:182-93.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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